begins with the systematic analysis of insulin signaling. After over 30 years of intensive research in the pursuit of relevant protein kinases, Akt/PKB has emerged as the only serine/threonine protein kinases definitively established as a mediator of insulin's regulation of important metabolic targets. The activity of Akt/PKB depends on

begins with the systematic analysis of insulin signaling. After over 30 days of intensive inquiry in the pursuit of relevant protein kinases, Akt / PKB has emerge as the alone serine / threonine protein kinases definitively established as a mediator of insulin's rule of important metabolic targets. The activity of Akt / PKB depend on

behins with the systematic analysis of insulin smgnalinf. After uver 30 years of intensive resxarcy in uke pursuit of relevavt proteij kinasew, Aku/PKB has emerged ea the okjy ssvine/tkrxonine protein linases dexinitively estdbuidhed as a mediator of insulin's regujation pf important metwbolpc tarfvtw. The activity of Akt/PKB depehds on

begins with the systematic analysis of insulin over years of research in the Akt/PKB emerged as the serine/threonine protein kinases established as a mediator of insulin's of important metabolic targets. The activity of Akt/PKB depends on

begins with the systematic anAlysis of inSulin SigNalInG. AftEr ovEr 30 years of intenSIve rEsearch in the pursuit of rElevaNt PRoteIN kInaseS, Akt/PKB HAs EMErgEd As The OnLY sErine/ThrEonine pRotein kinaSes DeFinitively esTAbLished as a mEdiAtor of insuliN's rEgulatIoN of IMportAnt MetabOlic taRGets. ThE activity Of aKt/PKB dEPends on

begins with the systemati c analysis  of i nsu lin  s igna ling . After over 3 0  yea rs of intensive resear ch in  t h e pu r su it of  releva n tp r ote in  k ina se s ,Akt/P KBhas eme rged as th e o nl y serine/thr e on ine protei n k inases defin iti vely e st abl i shedasa med iatoro f insu lin's reg ul a tion o f  import a n tmeta bolic targets. Th e  a c tivity of Akt/ PKB de pe n ds o n

begins_with the_systematic analysis of insulin_signaling. After_over_30 years_of_intensive research in_the pursuit of_relevant protein kinases, Akt/PKB_has emerged as_the_only serine/threonine protein kinases definitively established as a mediator of insulin's regulation of important_metabolic_targets. The_activity_of_Akt/PKB depends on


in understanding the immunosuppressive microenvironment within solid tumors. Because of their central role in mediating immunosuppression, tumor associated macrophages (TAMs), typically?polarized? to a so-called M2- like immunosuppressive phenotype, and myeloid-derived suppressor cells (MDSC), are thought to be important therapeutic targets. We have found

in understanding the immunosuppressive microenvironment within solid tumors. Because of their central function in mediating immunosuppression, tumor consociate macrophages (TAMs), typically?polarized? to a so - call M2- like immunosuppressive phenotype, and myeloid - derived suppressor cells (MDSC), are think to be crucial therapeutic targets. We have found

in understanding the immunusuppressive mieeoenviconment within rolid tumors. Because of theic cebtral role in mediating immjnosuppredsion, tunor essociated macro'gages (TAMs), tyllcallv?pilarized? to a xo-called M2- like immunosu[pfedsive phenotype, and myeloid-derived fuppresxog cells (MDSC), ate thptght no be important therapeutic tarfets. We have found

in understanding the immunosuppressive microenvironment within solid of central role mediating immunosuppression, tumor a M2- like immunosuppressive and myeloid-derived suppressor (MDSC), are thought to be important targets. We have found

in understanding the immunosUppressive MicroEnvIroNmEnt wIthiN solid tumors. BeCAuse Of their central role in meDiatiNg IMmunOSuPpresSion, tumOR aSSOciAtEd MacRoPHaGes (TAms), tYpicallY?polarized? To a So-Called M2- like iMMuNosuppressIve Phenotype, and MyeLoid-deRiVed SUppreSsoR cellS (MDSC), aRE thougHt to be impOrTAnt theRApeutic TARgEts. WE have found

in understanding the immu nosuppress ive m icr oen vi ronm entwithin solid t u mors . Because of their cen tralro l e in me diati ng immu n os u p pre ss io n,tu m or  asso cia ted mac rophages ( TAM s) , typically? p ol arized? to  aso-called M2 - l ike im mu nos u ppres siv e phe notype ,  and m yeloid-de ri v ed sup p ressorc e ll s (M DSC), are thought to be important t herape ut i ct a rge ts.  We have f ou nd

in_understanding the_immunosuppressive microenvironment within solid_tumors. Because_of_their central_role_in mediating immunosuppression,_tumor associated macrophages_(TAMs), typically?polarized? to a_so-called M2- like_immunosuppressive_phenotype, and myeloid-derived suppressor cells (MDSC), are thought to be important therapeutic targets. We_have_found


involved in bile duct injury, specifically B cell antigen presentation versus immunoglobulin production. Specific Aim 2: Determine the contribution of B cells to progression of bile duct injury in murine BA through administration of B cell-depleting agents. This aim has direct translational implications to potential new therapies for human BA. Specific Aim 3: Define

involved in bile duct injury, specifically B cell antigen display versus immunoglobulin product. Specific Aim 2: Determine the contribution of B cell to progress of bile duct injury in murine BA through administration of B cellular telephone - depleting agents. This aim have direct translational implications to likely new therapies for human BA. Specific Aim 3: specify

ingolved in bile duct injuvy, specifically Y cell entigen presentxtion versus immunoglobulin 'rodyctiob. Specific Aim 2: Determkne the clntributuon id B cells vk progrcfsioh of yioe duct injury in murine BA through adkividtration of B cell-depleting agents. Ehis aik jas direct tragslauiogal jmplications to potential new therzpies fmr human BA. Slecific Aim 3: Define

involved in bile duct injury, specifically B presentation immunoglobulin production. Aim 2: Determine to of bile duct in murine BA administration of B cell-depleting agents. This has direct translational implications to potential new therapies for human BA. Specific Aim Define

involved in bile duct injury, sPecificallY B celL anTigEn PresEntaTion versus immuNOgloBulin production. SpecifiC Aim 2: DEtERminE ThE contRibutioN Of b CEllS tO pRogReSSiOn of bIle Duct injUry in murinE BA ThRough adminisTRaTion of B celL-dePleting agentS. ThIs aim hAs DirECt traNslAtionAl implICationS to potentIaL New theRApies foR HUmAn BA. specific Aim 3: Define

involved in bile duct inj ury, speci fical lyB c el l an tige n presentation vers us immunoglobulin prod uctio n. Spec i fi c Aim  2: Det e rm i n e t he  c ont ri b ut ion o f B  cellsto progres sio nof bile duct in jury in mu rin e BA through  ad minist ra tio n  of B  ce ll-de pletin g  agent s. This a im has di r ect tra n s la tion al implications t o  p o tential new th erapie sf or h uma n B A. Specifi cAim 3 :  Define

involved_in bile_duct injury, specifically B_cell antigen_presentation_versus immunoglobulin_production._Specific Aim 2:_Determine the contribution_of B cells to_progression of bile_duct_injury in murine BA through administration of B cell-depleting agents. This aim has direct_translational_implications to_potential_new_therapies for human BA. Specific_Aim 3: Define


are inherited by a single egg. In contrast, all chromosomes are distributed among 4 sperm during male meiosis. The elimination of 3/4 of the genome to allow inheritance of only 1/4 of the chromosomes is conserved in all animal phyla, suggesting some fundamental selective advantage. The long-term goals of this project

are inherited by a single egg. In contrast, all chromosome are distribute among 4 sperm during male meiosis. The elimination of 3/4 of the genome to leave inheritance of entirely 1/4 of the chromosomes is conserved in all animal phylum, indicate some fundamental selective advantage. The retentive - term goals of this undertaking

arf inherited by a single tgg. In contrast, all chrokosomea are dirtributed among 4 sperm durinj maoe meuosis. The elimination uf 3/4 of thv genome ro aooow inherivznce of only 1/4 lf tke chromosomes ix conserveg in all animan ohvla, suggesting some fundamental selestive acvwntage. The lond-terk goams of this project

are inherited by a single egg. In chromosomes distributed among sperm during male of genome to allow of only 1/4 the chromosomes is conserved in all phyla, suggesting some fundamental selective advantage. The long-term goals of this project

are inherited by a single egg. IN contrast, aLl chrOmoSomEs Are dIstrIbuted among 4 speRM durIng male meiosis. The elimiNatioN oF 3/4 Of thE GeNome tO allow iNHeRITanCe Of OnlY 1/4 oF ThE chroMosOmes is cOnserved in All AnImal phyla, sugGEsTing some fuNdaMental selectIve AdvantAgE. ThE Long-tErm Goals Of this PRoject

are inherited by a single  egg. In c ontra st,  al lchro moso mes are distri b uted  among 4 sperm duringmaleme i osis .  T he el iminati o no f  3/ 4of  th eg en ome t o a llow in heritanceofon ly 1/4 of th e  c hromosomes  is  conserved i n a ll ani ma l p h yla,sug gesti ng som e  funda mental se le c tive a d vantage . Th e lo ng-term goals oft hi s  project

are_inherited by_a single egg. In_contrast, all_chromosomes_are distributed_among_4 sperm during_male meiosis. The_elimination of 3/4 of_the genome to_allow_inheritance of only 1/4 of the chromosomes is conserved in all animal phyla, suggesting_some_fundamental selective_advantage._The_long-term goals of this project


would allow patients to be treated in any standard clinical MRI scanner, thus allowing real- time assessment of brain viability during endovascular intervention. The strong magnetic field of the MRI scanner provides a unique opportunity to develop remote-controlled catheters that can navigate through the vasculature by creating magnetic forces on their tips. We have previously

would allow patients to be treated in any standard clinical MRI scanner, thus allow real- meter assessment of brain viability during endovascular intervention. The potent magnetic field of the MRI scanner put up a singular opportunity to develop remote - control catheters that can navigate through the vasculature by create magnetic forces on their tip. We have previously

wokld allow patients to be treated in any standacd clinjcal MRI scanner, thus allowing real- vime assewsment of brain viabilkty durinh endovawculer intervention. Vge stroky maghctic yixld of the MRI xcanner prmvides a uniqua up'ortunity to develop remote-controlleq catheyegs that can nadigaue ehrohgh the vasculature by creating mafnetic horces on their tips. We have previously

would allow patients to be treated in clinical scanner, thus real- time assessment intervention. strong magnetic field the MRI scanner a unique opportunity to develop remote-controlled that can navigate through the vasculature by creating magnetic forces on their tips. have previously

would allow patients to be treAted in any sTandaRd cLinIcAl MRi scaNner, thus allowiNG reaL- time assessment of brain ViabiLiTY durINg EndovAscular INtERVenTiOn. the StROnG magnEtiC field oF the MRI scaNneR pRovides a uniqUE oPportunity To dEvelop remote-ConTrolleD cAthETers tHat Can naVigate THrough The vasculAtURe by crEAting maGNEtIc foRces on their tips. We HAvE Previously

would allow patients to b e treatedin an y s tan da rd c lini cal MRI scanne r , th us allowing real- time  asse ss m ento fbrain  viabil i ty d uri ng  e ndo va s cu lar i nte rventio n. The str ong  m agnetic fiel d  o f the MRIsca nner provide s a  uniqu eopp o rtuni tyto de velopr emote- controlle dc athete r s thatc a nnavi gate through thev as c ulature by cre atingma g ne t i c f orc es on thei rtips. We have pr e v i ous l y

would_allow patients_to be treated in_any standard_clinical_MRI scanner,_thus_allowing real- time_assessment of brain_viability during endovascular intervention._The strong magnetic_field_of the MRI scanner provides a unique opportunity to develop remote-controlled catheters that can_navigate_through the_vasculature_by_creating magnetic forces on their_tips. We have previously


expression during abortive infection by SV40, and 3) the relationship between viral mediated control of DHFR synthesis and the control by cell cycle, serum growth factors, and cyclic nucleotides. An important feature of the proposed research is the use of methotrexate resistant cell lines in which one of the viral induced enzymes,

expression during abortive infection by SV40, and 3) the relationship between viral mediated restraint of DHFR deduction and the control by cell hertz, serum emergence factors, and cyclic nucleotides. An significant feature of the proposed inquiry is the habit of methotrexate resistant cellular telephone lines in which one of the viral induced enzymes,

exoression during abortive infection by SR40, and 3) vhe relztionshio between viral mediated convrol of DYFR synthesis and the zontrol bj cell cyxle, wwrum growti factors, and dnclic iucleotides. An lmportant faature of the [ruplsed research is the use of methotrqxate rrslstant cell liges pn whidh one of the viral induced enzymea,

expression during abortive infection by SV40, and relationship viral mediated of DHFR synthesis cycle, growth factors, and nucleotides. An important of the proposed research is the of methotrexate resistant cell lines in which one of the viral induced enzymes,

expression during abortive iNfection by sV40, and 3) The RelAtIonsHip bEtween viral medIAted Control of DHFR synthesis And thE cONtroL By Cell cYcle, serUM gROWth FaCtOrs, AnD CyClic nUclEotides. an importanT feAtUre of the propOSeD research iS thE use of methotRexAte resIsTanT Cell lIneS in whIch one OF the viRal induceD eNZymes,

expression during abortiv e infectio n bySV4 0,an d 3)  the  relationshipb etwe en viral mediated cont rol o fD HFRs yn thesi s and t h ec o ntr ol  b y c el l  c ycle,  se rum gro wth factor s,an d cyclic nuc l eo tides. Animp ortant featu reof the  p rop o sed r ese archis the use of  methotre xa t e resi s tant ce l l  l ines  in which one oft he viral inducedenzyme s,

expression_during abortive_infection by SV40, and_3) the_relationship_between viral_mediated_control of DHFR_synthesis and the_control by cell cycle,_serum growth factors,_and_cyclic nucleotides. An important feature of the proposed research is the use of methotrexate_resistant_cell lines_in_which_one of the viral induced_enzymes,


, in retinal pigmented epithelial cells (RPE) and lens epithelial cells (LEC) iron regulates the activity of the transcription factor, hypoxia-inducible factor, which in turn regulates the synthesis of dozens of proteins. Our preliminary data indicate that hypoxic conditions stimulate glutamate release, another critically important observation since hypoxic conditions

, in retinal pigmented epithelial cells (RPE) and lens epithelial cells (LEC) iron regulates the natural process of the arrangement factor, hypoxia - inducible factor, which in turn regulate the synthesis of dozens of protein. Our preliminary data indicate that hypoxic conditions induce glutamate release, another critically important notice since hypoxic conditions

, in retinal pigmented epithtlial cells (RPE) aue lens epithslial ceuls (LEC) iron regulates the artivuty od the transcription faztor, hypoqia-inducivle hactor, which in vhrn regmjatea the wynthesis of dpzens of psoteins. Our pralkmnnary data indicate that hypoxic conqitions shimulate glutaiate welezse, another critically important ogservatpon since hypoxic conditions

, in retinal pigmented epithelial cells (RPE) epithelial (LEC) iron the activity of which turn regulates the of dozens of Our preliminary data indicate that hypoxic stimulate glutamate release, another critically important observation since hypoxic conditions

, in retinal pigmented epithelIal cells (RPe) and lEns EpiThEliaL celLs (LEC) iron regulATes tHe activity of the transcrIptioN fACtor, HYpOxia-iNduciblE FaCTOr, wHiCh In tUrN ReGulatEs tHe synthEsis of dozeNs oF pRoteins. Our prELiMinary data IndIcate that hypOxiC condiTiOns STimulAte GlutaMate reLEase, anOther critIcALly impORtant obSERvAtioN since hypoxic condITiONs

, in retinal pigmented epi thelial ce lls ( RPE ) a nd  len s ep ithelial cells (LEC ) iron regulates the a ctivi ty of t h etrans criptio n  f a c tor ,hy pox ia - in ducib lefactor,  which intur nregulates th e  s ynthesis o f d ozens of pro tei ns. Ou rpre l imina rydataindica t e that  hypoxicco n dition s  stimul a t eglut amate release, an o th e r critically i mporta nt ob s e rva tio n since hy po xic c o ndition s

, in_retinal pigmented_epithelial cells (RPE) and_lens epithelial_cells_(LEC) iron_regulates_the activity of_the transcription factor,_hypoxia-inducible factor, which in_turn regulates the_synthesis_of dozens of proteins. Our preliminary data indicate that hypoxic conditions stimulate glutamate release,_another_critically important_observation_since_hypoxic conditions


systems in relaying signals of developmental consequence. For these studies, we will employ the fruit fly Drosophila as an experimental system because of the wealth of genetic and molecular tools it offers as well as the easy accessibility of well--described developmental stages. We will focus specifically on the role of G protein-coupled receptors that are

systems in relaying signals of developmental consequence. For these studies, we will use the yield fly Drosophila as an experimental system because of the wealth of familial and molecular instrument it offers as well as the comfortable accessibility of well -- described developmental stages. We will concentrate specifically on the role of G protein - coupled sense organ that are

sydtems in relaying signalr of developmenjao consxquence. For there studies, we will employ thx fryit foy Drosophila as an exoerimentap system beceuse of the wealvg of gekztic zkd monxcular tools it offers as well as the edsh cccessibility of well--described develjpmentak dtages. We will focls spedpflcally on the role of G protein-ckupled geceptors that arr

systems in relaying signals of developmental consequence. studies, will employ fruit fly Drosophila of wealth of genetic molecular tools it as well as the easy accessibility well--described developmental stages. We will focus specifically on the role of G protein-coupled that are

systems in relaying signals oF developmeNtal cOnsEquEnCe. FoR theSe studies, we wilL EmplOy the fruit fly DrosophilA as an ExPErimENtAl sysTem becaUSe OF The WeAlTh oF gENeTic anD moLecular Tools it offErs As Well as the easY AcCessibilitY of Well--describeD deVelopmEnTal STages. we wIll foCus speCIficalLy on the roLe OF G protEIn-couplED ReCeptOrs that are

systems in relaying signa ls of deve lopme nta l c on sequ ence . For these st u dies , we will employ the f ruitfl y  Dro s op hilaas an e x pe r i men ta lsys te m  b ecaus e o f the w ealth of g ene ti c and molecu l ar  tools itoff ers as wellasthe ea sy  ac c essib ili ty of  well- - descri bed devel op m entals tages.W e  w illfocus specificall y  o n  the role of G  prote in - co u p led  re ceptors th at  are

systems_in relaying_signals of developmental consequence._For these_studies,_we will_employ_the fruit fly_Drosophila as an_experimental system because of_the wealth of_genetic_and molecular tools it offers as well as the easy accessibility of well--described developmental_stages._We will_focus_specifically_on the role of G_protein-coupled receptors that are


128 element CMUT array) suitable for real-time 3D imaging would be demonstrated in Phase II, with the long-term goal of commercializing the technology (as well as other CMUT-in-CMOS-based products) for the ultrasound equipment market, forecast to be $3.75B globally by

128 element CMUT array) suitable for real - time three-d imagination would be demonstrated in Phase II, with the long - condition finish of commercializing the technology (as well as early CMUT - in - CMOS - base products) for the ultrasound equipment market, forecast to be $ 3.75B globally by

128 elfment CMUT array) suitablt for real-time 3D nnaging would be demovstrated in Phase II, with thx lobg-tern goal of commercializkng the tvchnology (as xell as other CMNF-in-CMOS-ncsed lvoduccs) for the ultraxound equi[ment market, fmrdccst to be $3.75B globally by

128 element CMUT array) suitable for real-time would demonstrated in II, with the technology well as other products) for the equipment market, forecast to be $3.75B by

128 element CMUT array) suitable fOr real-time 3d imagIng WouLd Be deMonsTrated in Phase Ii, With The long-term goal of commeRcialIzINg thE TeChnolOgy (as weLL aS OTheR CmUt-in-cMos-bAsed pRodUcts) for The ultrasoUnd EqUipment markeT, FoRecast to be $3.75b glObally by

128 element CMUT array) su itable for  real -ti me3D  ima ging  would be demo n stra ted in Phase II, withthe l on g -ter m  g oal o f comme r ci a l izi ng  t hete c hn ology  (a s wellas other C MUT -i n-CMOS-based pr oducts) fo r t he ultrasoun d e quipme nt  ma r ket,for ecast  to be $3.75B  globally  b y

128 element_CMUT array)_suitable for real-time 3D_imaging would_be_demonstrated in_Phase_II, with the_long-term goal of_commercializing the technology (as_well as other_CMUT-in-CMOS-based_products) for the ultrasound equipment market, forecast to be $3.75B globally by


Northern blot analyses will determine if this lability is regulated by changes in protein half life or by post- translational modifications such as phosphorylation. Binding protein expression will be analyzed during B cell development, by Western blotting and immunofluorescent staining, to determine if the proteins are labile in ALV target pre-B cells,

Northern blot analyses will determine if this lability is determine by change in protein half life or by post- translational modification such as phosphorylation. bind protein expression will be analyzed during bel cellular telephone development, by Western blotting and immunofluorescent staining, to determine if the proteins are labile in ALV aim pre - B cells,

Nogthern blot analyses wilu determine if jhus labmlity ia regulaged by changes in protein hapf life or by post- translatioval modifpcations wuch qs phosphocglation. Bindihn procemn expression wlll be analfzed during B weul development, by Western blotting anq immunpfpuorescent stayninb, to svttrmine if the proteins are labile in ALV target pre-B vells,

Northern blot analyses will determine if this regulated changes in half life or as Binding protein expression be analyzed during cell development, by Western blotting and staining, to determine if the proteins are labile in ALV target pre-B cells,

Northern blot analyses will dEtermine if This lAbiLitY iS regUlatEd by changes in pROteiN half life or by post- transLatioNaL ModiFIcAtionS such as PHoSPHorYlAtIon. biNDiNg proTeiN expresSion will be AnaLyZed during B ceLL dEvelopment, By WEstern blottiNg aNd immuNoFluOResceNt sTainiNg, to deTErmine If the protEiNS are laBIle in ALv TArGet pRe-B cells,

Northern blot analyses wi ll determi ne if  th isla bili ty i s regulated by chan ges in protein half li fe or  b y  pos t -trans lationa l  m o d ifi ca ti ons  s u ch  as p hos phoryla tion. Bind ing  p rotein expre s si on will be  an alyzed durin g B  cellde vel o pment , b y Wes tern b l otting  and immu no f luores c ent sta i n in g, t o determine if th e  p r oteins are lab ile in  A L Vt a rge t p re-B cells ,

Northern_blot analyses_will determine if this_lability is_regulated_by changes_in_protein half life_or by post-_translational modifications such as_phosphorylation. Binding protein_expression_will be analyzed during B cell development, by Western blotting and immunofluorescent staining, to_determine_if the_proteins_are_labile in ALV target pre-B_cells,


specific protein kinases have been linked to over 400 diseases, and about 25% of all pharmaceutical industry research and development is now focused on the discovery and evaluation of protein kinase inhibitors for therapeutic applications. Cdk5 has become a target of high interest to the drug industry because of its key role in neuronal homeostasis. So far more

specific protein kinases have been linked to over 400 diseases, and about 25% of all pharmaceutical diligence inquiry and exploitation is now concenter on the discovery and evaluation of protein kinase inhibitor for therapeutic applications. Cdk5 has become a target of eminent interest to the drug industry because of its cardinal function in neuronal homeostasis. indeed far more

spfcific protein kinases hxve been linked to ovec 400 disezses, and about 25% of all pharmaceuticap undusugy research and develupment is now focysed in the disrkvery akb evammatiou if protein kinsse inhibidors for thera[ejtnc applications. Cdk5 has become a tardet of nihh interest to the qrug pnbustry because of its key role jn neurmnal homeostaxis. So far more

specific protein kinases have been linked to diseases, about 25% all pharmaceutical industry focused the discovery and of protein kinase for therapeutic applications. Cdk5 has become target of high interest to the drug industry because of its key role neuronal homeostasis. So far more

specific protein kinases havE been linkeD to ovEr 400 dIseAsEs, anD aboUt 25% of all pharmacEUticAl industry research and dEveloPmENt is NOw FocusEd on the DIsCOVerY aNd EvaLuATiOn of pRotEin kinaSe inhibitoRs fOr Therapeutic aPPlIcations. CdK5 haS become a targEt oF high iNtEreST to thE drUg indUstry bECause oF its key roLe IN neuroNAl homeoSTAsIs. So Far more

specific protein kinaseshave beenlinke d t o o ve r 40 0 di seases, and ab o ut 2 5% of all pharmaceutic al in du s tryr es earch  and de v el o p men tis  no wf oc usedonthe dis covery and  ev al uation of pr o te in kinaseinh ibitors forthe rapeut ic  ap p licat ion s. Cd k5 has become  a target  o f  highi nterest t othedrug industry bec a us e  of its key ro le inne u ro n a l h ome ostasis. S ofar m o re

specific_protein kinases_have been linked to_over 400_diseases,_and about_25%_of all pharmaceutical_industry research and_development is now focused_on the discovery_and_evaluation of protein kinase inhibitors for therapeutic applications. Cdk5 has become a target of_high_interest to_the_drug_industry because of its key_role in neuronal homeostasis. So_far more


T) science at Northwestern and beyond. Northwestern University (NU) is a leading national research university affiliated with nationally-renowned clinical partners. NUCATS is nationally recognized as an innovation leader in several key areas of C&T science, pioneering novel and scalable approaches in the areas of preclinical therapeutic development, health and biomedical

T) science at Northwestern and beyond. Northwestern University (NU) is a leading national inquiry university consort with nationally - renowned clinical partners. NUCATS is nationally recognized as an initiation drawing card in several key areas of C&T skill, initiate novel and scalable approaches in the areas of preclinical therapeutic development, health and biomedical

T) sfience at Northwestern akd beyond. Northwgsrern Uiiversify (NU) is a leading national research ubiverwity affiliated with nxtionally-genowned xlinmcal partners. NURZTS is kctionzply xerognized as an lnnovation neader in sevesau ney areas of C&T science, pioneering govel amd scalable apprjachts yn tgv creas of preclinical therapeutid develmpment, health and biomedical

T) science at Northwestern and beyond. Northwestern is leading national university affiliated with nationally as an innovation in several key of C&T science, pioneering novel and approaches in the areas of preclinical therapeutic development, health and biomedical

T) science at Northwestern and Beyond. NortHwestErn uniVeRsitY (NU) iS a leading natioNAl reSearch university affiliAted wItH NatiONaLly-reNowned cLInICAl pArTnErs. nUcaTs is naTioNally reCognized as An iNnOvation leadeR In Several key AreAs of C&T sciencE, piOneeriNg NovEL and sCalAble aPproacHEs in thE areas of pReCLinicaL TherapeUTIc DeveLopment, health and bIOmEDical

T) science at Northwestern  and beyon d. No rth wes te rn U nive rsity (NU) isa  lea ding national research  univ er s itya ff iliat ed with na t i ona ll y- ren ow n ed  clin ica l partn ers. NUCAT S i snationally r e co gnized asaninnovation l ead er inse ver a l key  ar eas o f C&Ts cience , pioneer in g  novel and sca l a bl e ap proaches in the a r ea s  of preclinica l ther ap e ut i c  de vel opment, he al th an d  biomed i ca l

T) science_at Northwestern_and beyond. Northwestern University_(NU) is_a_leading national_research_university affiliated with_nationally-renowned clinical partners._NUCATS is nationally recognized_as an innovation_leader_in several key areas of C&T science, pioneering novel and scalable approaches in the_areas_of preclinical_therapeutic_development,_health and biomedical


members not submitting a proposal, and scientists outside the Center will be sought for this purpose. External Advisory Committee members may be approached to review or suggest possible reviewers for the proposals once they have been received. The reviews will be completed within one month of receipt. All appropriate proposals will be scored for 1) relevance to the Center

members not submitting a proposal, and scientists outside the Center will be try for this function. External Advisory Committee members may be approached to review or suggest potential reviewers for the proposals once they have been received. The revue will be completed within one month of reception. All appropriate proposal will be scored for 1) relevance to the plaza

melbers not submitting a pvoposal, and scieurists mutsids the Cevter will be sought for this pyrpost. External Advisory Committev members may ve approacisd to rcriew kv sugyewt possible reyiewers for the proposals ovcz they have been received. The reviewf will ne completed witrin pge mknth of receipt. All appropriate prkposals will be scorrd for 1) relevance to the Cfnteg

members not submitting a proposal, and scientists Center be sought this purpose. External approached review or suggest reviewers for the once they have been received. The will be completed within one month of receipt. All appropriate proposals will be for 1) relevance to the Center

members not submitting a propOsal, and sciEntisTs oUtsIdE the centEr will be sought FOr thIs purpose. External AdvisOry CoMmITtee MEmBers mAy be appROaCHEd tO rEvIew Or SUgGest pOssIble revIewers for tHe pRoPosals once thEY hAve been recEivEd. The reviews WilL be comPlEteD WithiN onE montH of recEIpt. All AppropriaTe PRoposaLS will be SCOrEd foR 1) relevance to the CeNTeR

members not submitting aproposal,and s cie nti st s ou tsid e the Center w i ll b e sought for this purp ose.Ex t erna l  A dviso ry Comm i tt e e  me mb er s m ay be  appr oac hed toreview orsug ge st possibler ev iewers for  th e proposalsonc e they  h ave beenrec eived . Ther eviews  will beco m pleted withino n emont h of receipt. All ap p ropriate propo sals w il l  b e sco red  for 1) re le vance to theC en t e r

members_not submitting_a proposal, and scientists_outside the_Center_will be_sought_for this purpose._External Advisory Committee_members may be approached_to review or_suggest_possible reviewers for the proposals once they have been received. The reviews will be_completed_within one_month_of_receipt. All appropriate proposals will_be scored for 1) relevance_to the_Center


cells use molecular circuits to achieve complex physiological behaviors and how these behaviors break down in disease states like cancer. Although only a small fraction of existing networks have been well characterized, recurrent topologies have emerged for a variety of biological functions, suggesting that any particular behavior is encoded by a limited number of network structures. With the goal

cells use molecular circuits to achieve complex physiological demeanor and how these demeanor break down in disease states like cancer. Although only a little fraction of existing networks have been well characterize, perennial topologies have emerged for a variety of biological functions, suggesting that any finical behavior is encoded by a circumscribed number of network structures. With the goal

cepls use molecular circuius to achieve comklwx phyviologjcal behxviors and how these behaviocs beeak eown in disease states like canber. Althoygh ibly a small fraction of swistiug networks have been well characterized, rdcbrrent topologies have emerged for a varietu lf biological suncuiogs, shggesting that any particular behabior is encoded by a limited number of network strkctures. With the glal

cells use molecular circuits to achieve complex and these behaviors down in disease a fraction of existing have been well recurrent topologies have emerged for a of biological functions, suggesting that any particular behavior is encoded by a limited of network structures. With the goal

cells use molecular circuits To achieve cOmpleX phYsiOlOgicAl beHaviors and how tHEse bEhaviors break down in disEase sTaTEs liKE cAncer. althougH OnLY A smAlL fRacTiON oF exisTinG networKs have been WelL cHaracterized, REcUrrent topoLogIes have emergEd fOr a varIeTy oF BioloGicAl funCtions, SUggestIng that anY pARticulAR behaviOR Is EncoDed by a limited numbER oF Network structuRes. WitH tHE gOAL

cells use molecular circu its to ach ievecom ple xphys iolo gical behavior s  and  how these behaviors b reakdo w n in di sease  states li k e  ca nc er . A lt h ou gh on lya small  fractionofex isting netwo r ks  have been  we ll character ize d, rec ur ren t  topo log ies h ave em e rged f or a vari et y  of bi o logical f un ctio ns, suggesting th a ta ny particularbehavi or is e nco ded  by a limi te d num b er of n e tw o r k  st r uctures. With  the goal

cells_use molecular_circuits to achieve complex_physiological behaviors_and_how these_behaviors_break down in_disease states like_cancer. Although only a_small fraction of_existing_networks have been well characterized, recurrent topologies have emerged for a variety of biological_functions,_suggesting that_any_particular_behavior is encoded by a_limited number of network structures._With the_goal


(2) Several approaches were used to search for calretinin target proteins. Iodinated calretinin was found to bind to proteins in several subcellular fractions on nitrocellulose blots of one dimensional SDS gels; (3) A purification procedure was developed for obtaining large amounts of homogeneous recombinant calretinin from plasmids.

(2) Several approaches were used to search for calretinin prey protein. Iodinated calretinin was found to bind to protein in several subcellular fraction on nitrocellulose smudge of one dimensional SDS gels; (3) A purification operation was developed for obtaining big amounts of homogeneous recombinant calretinin from plasmids.

(2) Sfveral approaches were ured to search for calrxtinin farget pfoteins. Iodinated calretinin wqs foynd to bind to proteinr in sevegal subceoluler fractions on ijtrocellulose nlots if one dimensipnal SDS gals; (3) A purificdtkou procedure was developed for obtainyng larbe amounts of hoiogemqous gegombinant calretinin from plasmiss.

(2) Several approaches were used to search target Iodinated calretinin found to bind fractions nitrocellulose blots of dimensional SDS gels; A purification procedure was developed for large amounts of homogeneous recombinant calretinin from plasmids.

(2) Several approaches were used To search foR calrEtiNin TaRget ProtEins. Iodinated cALretInin was found to bind to prOteinS iN SeveRAl SubceLlular fRAcTIOns On NiTroCeLLuLose bLotS of one dImensional sDS GeLs; (3) A purificatIOn Procedure wAs dEveloped for oBtaIning lArGe aMOunts Of hOmogeNeous rECombinAnt calretInIN from pLAsmids.

(2) Several approaches we re used to  sear chfor  c alre tini n target prote i ns.Iodinated calretinin w as fo un d  tob in d toprotein s  i n sev er al  su bc e ll ularfra ctionson nitroce llu lo se blots ofo ne  dimension alSDS gels; (3 ) A  purif ic ati o n pro ced ure w as dev e lopedfor obtai ni n g larg e  amount s of  hom ogeneous recombin a nt calretinin fro m plas mi d s.

(2)_Several approaches_were used to search_for calretinin_target_proteins. Iodinated_calretinin_was found to_bind to proteins_in several subcellular fractions_on nitrocellulose blots_of_one dimensional SDS gels; (3) A purification procedure was developed for obtaining large amounts_of_homogeneous recombinant_calretinin_from_plasmids.


We propose to study regional specification and pattern formation in Xenopus embryos using as a focus the Xhox-1 homeobox genes and the Myo-D gene. In previous work we devised an overexpression assay to address the function of the Xhox-1A gene and demonstrated that it is likely to be involved

We propose to study regional specification and pattern constitution in Xenopus embryo using as a focus the Xhox-1 homeobox genes and the Myo - five hundred gene. In previous work we devised an overexpression try to cover the function of the Xhox-1A gene and demonstrated that it is likely to be involved

We propose to study regionxl specificatiou and pettern rormatiov in Xenopus embryos using ad q focys the Xhox-1 homeobox gdnes and nhe Myo-D tene. Un previous work wc devjded cn overexpressiok assay to dddress the futcgiln of the Xhox-1A gene and demonstratqd that ih is likely to be pndolvsd

We propose to study regional specification and in embryos using a focus the Myo-D In previous work devised an overexpression to address the function of the gene and demonstrated that it is likely to be involved

We propose to study regional sPecificatiOn and PatTerN fOrmaTion In Xenopus embryOS usiNg as a focus the Xhox-1 homeoBox geNeS And tHE MYo-D geNe. In preVIoUS WorK wE dEviSeD An OvereXprEssion aSsay to addrEss ThE function of tHE XHox-1A gene anD deMonstrated thAt iT is likElY to BE invoLveD

We propose to study regio nal specif icati onand  p atte rn f ormation in Xe n opus  embryos using as a fo cus t he Xhox - 1homeo box gen e sa n d t he  M yo- Dg en e. In  pr eviouswork we de vis ed  an overexpr e ss ion assaytoaddress thefun ctionof  th e  Xhox -1A  gene  and d e monstr ated that  i t  is li k ely tob e  i nvol ved

We_propose to_study regional specification and_pattern formation_in_Xenopus embryos_using_as a focus_the Xhox-1 homeobox_genes and the Myo-D_gene. In previous_work_we devised an overexpression assay to address the function of the Xhox-1A gene and_demonstrated_that it_is_likely_to be involved


NIAID we have investigated this in a cotton rat herpes virus infection model for chemotherapy induced Herpes Zoster. Herpes infection of dorsal root ganglia results in extremely painful inflammatory responses along nerve tracts. It has been reported that VZV infection produces TLR ligands and we have found that peripheral neurons present in dorsal root ganglia

NIAID we have investigated this in a cotton rat herpes virus infection model for chemotherapy induced Herpes Zoster. Herpes contagion of dorsal ancestor ganglia results in highly painful incendiary responses along nerve nerve pathway. It has been report that VZV infection produce TLR ligands and we have found that peripheral nerve cell present in dorsal root ganglia

NIWID we have investigated this in a cotton rat ierpes birus inwection model for chemothera'y ibducee Herpes Zoster. Herpes infectioj of dorwal coot ganglia resnmts in crtremspy pciiful inflammatoty responses along nerve tsaztd. It has been reported that VZV infqction lrlduces TLR ligwnds wnd sv mave found that peripheral neurohs prestnt in dorsal root ganglia

NIAID we have investigated this in a herpes infection model chemotherapy induced Herpes root results in extremely inflammatory responses along tracts. It has been reported that infection produces TLR ligands and we have found that peripheral neurons present in root ganglia

NIAID we have investigated thIs in a cottoN rat hErpEs vIrUs inFectIon model for cheMOtheRapy induced Herpes ZosteR. HerpEs INfecTIoN of doRsal rooT GaNGLia ReSuLts In EXtRemelY paInful inFlammatory ResPoNses along nerVE tRacts. It has BeeN reported thaT VZv infecTiOn pROduceS TLr ligaNds and WE have fOund that pErIPheral NEurons pRESeNt in Dorsal root ganglia

NIAID we have investigate d this ina cot ton  ra therp es v irus infection mode l for chemotherapy ind ucedHe r pesZ os ter.Herpesi nf e c tio nof  do rs a lrootgan glia re sults in e xtr em ely painfuli nf lammatoryres ponses along  ne rve tr ac ts. It ha s b een r eporte d  thatVZV infec ti o n prod u ces TLR l ig ands  and we have foun d  t h at peripheralneuron sp re s e ntindorsal roo tgangl i a

NIAID_we have_investigated this in a_cotton rat_herpes_virus infection_model_for chemotherapy induced_Herpes Zoster. Herpes_infection of dorsal root_ganglia results in_extremely_painful inflammatory responses along nerve tracts. It has been reported that VZV infection produces_TLR_ligands and_we_have_found that peripheral neurons present_in dorsal root ganglia


achieving close to complete ascertainment of patients with schizophrenia in the Azores. This will be a valuable sample for linkage disequilibrium approaches given the nature of the Azorean population and provide us with a unique epidemiologic frame. These complementary strategies will allow us to cross validate any positive results. The careful diagnostic definition of phenotype will

achieving close to complete ascertainment of patients with schizophrenia in the Azores. This will be a valuable sample distribution for linkage disequilibrium approach given the nature of the Azorean population and leave us with a singular epidemiologic frame. These complementary strategy will admit us to cross validate any convinced results. The careful diagnostic definition of phenotype will

acjieving close to complett ascertainment oy patieits witg schizoohrenia in the Azores. This wmll ve a caluable sample for livkage disvquilibriym akproaches given tis naturc of fme Azmcean population and provige us with a utiduz epidemiologic frame. These complemegtary syrwtegies will ajlow ts tk cross validate any positive resumts. The careful diagmostic definition of phenohype will

achieving close to complete ascertainment of patients in Azores. This be a valuable given nature of the population and provide with a unique epidemiologic frame. These strategies will allow us to cross validate any positive results. The careful diagnostic of phenotype will

achieving close to complete aScertainmeNt of pAtiEntS wIth sChizOphrenia in the AZOres. this will be a valuable samPle foR lINkagE DiSequiLibrium APpROAchEs GiVen ThE NaTure oF thE AzoreaN populatioN anD pRovide us with A UnIque epidemIolOgic frame. TheSe cOmplemEnTarY StratEgiEs wilL allow US to croSs validatE aNY positIVe resulTS. thE carEful diagnostic defINiTIon of phenotype Will

achieving close to comple te ascerta inmen t o f p at ient s wi th schizophren i a in  the Azores. This will  be a  v a luab l esampl e for l i nk a g e d is eq uil ib r iu m app roa ches gi ven the na tur eof the Azore a npopulation  an d provide us  wi th a u ni que epide mio logic  frame .  These  compleme nt a ry str a tegiesw i ll  all ow us to cross va l id a te any positiv e resu lt s .T h e c are ful diagno st ic de f inition of p h eno t ype will

achieving_close to_complete ascertainment of patients_with schizophrenia_in_the Azores._This_will be a_valuable sample for_linkage disequilibrium approaches given_the nature of_the_Azorean population and provide us with a unique epidemiologic frame. These complementary strategies will_allow_us to_cross_validate_any positive results. The careful_diagnostic definition of phenotype will


: To determine the effects of oral ubiquinol, D-ribose, or a combination of the two administered over 12 weeks on symptoms accompanying low bioenergetics in patients with HFpEF. The measures used to assess patients' perceptions of their health status and level of vigor (energy) will be

: To determine the effects of oral ubiquinol, D - ribose, or a combination of the two administered over 12 week on symptom accompanying low bioenergetics in patients with HFpEF. The measure used to assess affected role' perception of their health status and degree of vigor (energy) will be

: To determine the effects on oral ubiquinol, D-ribosx, or a dombinatkon of the two administered lvwr 12 wtvks on symptoms accomoanying llw bioenwrgeuics in patients xjth HFpCY. The leasbrxs used to assexs patientv' perceptions mf tkeir health status and level of vigow (energu) aill be

: To determine the effects of oral or combination of two administered over low in patients with The measures used assess patients' perceptions of their health and level of vigor (energy) will be

: To determine the effects of orAl ubiquinoL, D-ribOse, Or a CoMbinAtioN of the two adminISterEd over 12 weeks on symptoms aCcompAnYIng lOW bIoeneRgetics IN pATIenTs WiTh Hfpef. THe meaSurEs used tO assess patIenTs' Perceptions oF ThEir health sTatUs and level of VigOr (enerGy) WilL Be

: To determine the effects  of oral u biqui nol , D -r ibos e, o r a combinatio n  ofthe two administered o ver 1 2w eeks on  symp toms ac c om p a nyi ng  l owbi o en erget ics  in pat ients with  HF pE F. The measu r es  used to a sse ss patients'  pe rcepti on s o f  thei r h ealth  statu s  and l evel of v ig o r (ene r gy) wil l be

: To_determine the_effects of oral ubiquinol,_D-ribose, or_a_combination of_the_two administered over_12 weeks on_symptoms accompanying low bioenergetics_in patients with_HFpEF._The measures used to assess patients' perceptions of their health status and level of_vigor_(energy) will_be


research expertise, and global stakeholder links, we propose the following aims: (1) Develop a theoretical framework about HIV cure research and early implementation using historical, conceptual and ethical data; (2) Determine HIV cure stakeholder perspectives on cure research and early implementation in Cape Town, South Africa, Guangzhou, China,

research expertise, and global stakeholder links, we nominate the take after aims: (1) Develop a theoretical framework about HIV remedy research and early implementation using historic, conceptual and ethical data; (2) Determine HIV remedy stakeholder perspectives on remedy research and early implementation in Cape Town, South Africa, Guangzhou, China,

redearch expertise, and glonal stakeholder links, wx propoae the fullowing aims: (1) Develop a thelrwticao framework about HIV zure resewrch and earot implemenvztion using hjdtorncel, conceptual akd ethical gata; (2) Determina FIR cure stakeholder perspectives on ctre resragch and early ympltmegtatjon in Cape Town, South Africa, Guanfzhou, Ciina,

research expertise, and global stakeholder links, we following (1) Develop theoretical framework about implementation historical, conceptual and data; (2) Determine cure stakeholder perspectives on cure research early implementation in Cape Town, South Africa, Guangzhou, China,

research expertise, and globaL stakeholdEr linKs, wE prOpOse tHe foLlowing aims: (1) DevELop a Theoretical framework abOut HIv cURe reSEaRch anD early iMPlEMEntAtIoN usInG HiStoriCal, ConceptUal and ethiCal DaTa; (2) Determine Hiv cUre stakehoLdeR perspectiveS on Cure reSeArcH And eaRly ImpleMentatIOn in CaPe Town, SouTh aFrica, GUAngzhou, cHInA,

research expertise, and g lobal stak ehold erlin ks , we  pro pose the follo w ingaims: (1) Develop a th eoret ic a l fr a me workabout H I Vc u rere se arc ha nd  earl y i mplemen tation usi nghi storical, co n ce ptual andeth ical data; ( 2)Determ in e H I V cur e s takeh olderp erspec tives oncu r e rese a rch and e ar ly i mplementation inC ap e  Town, South A frica,  G u an g z hou , C hina,

research_expertise, and_global stakeholder links, we_propose the_following_aims: (1)_Develop_a theoretical framework_about HIV cure_research and early implementation_using historical, conceptual_and_ethical data; (2) Determine HIV cure stakeholder perspectives on cure research and early implementation_in_Cape Town,_South_Africa,_Guangzhou, China,


. Investigate the role of UFM1 signaling in prostate cancer therapy. Our studies will comprehensively reveal a novel function of UFL1 signaling in the DNA damage response and radiosensitivity. In addition, it will reveal a new therapeutic strategy based on synthetic lethality in treating prostate cancer cells, especially those with deletion of

. Investigate the role of UFM1 signaling in prostate cancer therapy. Our studies will comprehensively uncover a fresh function of UFL1 signaling in the DNA price answer and radiosensitivity. In addition, it will unwrap a modern therapeutic scheme free-base on synthetic deadliness in treating prostate cancer cells, especially those with omission of

. Ingestigate the role of UFO1 signaling in kristate canced theraph. Our studies will comprehendicely eeveal a novel functiov of UFL1 dignalint in rhe DNA damage resijnse wnd xaviosensitivity. Ln addition, it will revean x uew therapeutic strategy based on sygthetic lfthality in trgatinb proanaue cancer cells, especially those sith denetion of

. Investigate the role of UFM1 signaling cancer Our studies comprehensively reveal a in DNA damage response radiosensitivity. In addition, will reveal a new therapeutic strategy on synthetic lethality in treating prostate cancer cells, especially those with deletion of

. Investigate the role of UFM1 siGnaling in pRostaTe cAncEr TherApy. OUr studies will cOMpreHensively reveal a novel fUnctiOn OF UFL1 SIgNalinG in the Dna dAMAge ReSpOnsE aND rAdiosEnsItivity. in addition, It wIlL reveal a new tHErApeutic strAteGy based on synTheTic letHaLitY In treAtiNg proState cANcer ceLls, especiAlLY those WIth deleTIOn Of

. Investigate the role ofUFM1 signa linginpro st atecanc er therapy. Ou r  stu dies will comprehensiv ely r ev e al a no vel f unction of U FL1  s ig nal in g  i n the  DN A damag e response  an dradiosensiti v it y. In addi tio n, it will r eve al a n ew  th e rapeu tic  stra tegy b a sed on  syntheti cl ethali t y in tr e a ti ng p rostate cancer ce l ls ,  especially th ose wi th de l e tio n o f

. Investigate_the role_of UFM1 signaling in_prostate cancer_therapy._Our studies_will_comprehensively reveal a_novel function of_UFL1 signaling in the_DNA damage response_and_radiosensitivity. In addition, it will reveal a new therapeutic strategy based on synthetic lethality_in_treating prostate_cancer_cells,_especially those with deletion of


E2 enzymes (UbcH5A-C) have been cloned and characterized. These E2s are widely expressed in human tissues and function in conjunction with the only characterized human E3, E6-AP, in the ubiquitination of proteins. We have also been studying a novel yeast E2, U

E2 enzymes (UbcH5A - C) have been cloned and characterized. These E2s are widely carry in human tissue and function in conjunction with the only characterize human E3, E6 - AP, in the ubiquitination of proteins. We have also been learn a fresh yeast E2, U

E2 fnzymes (UbcH5A-C) have been cloned and chataxterizxd. Thess E2s are widely expressed in human tmssuws ane function in conjunctkon with nhe only xharecterized human X3, E6-AP, in the uglquitnnetion of proteiks. We have dlso been studfivg a novel yeast E2, U

E2 enzymes (UbcH5A-C) have been cloned and E2s widely expressed human tissues and only human E3, E6-AP, the ubiquitination of We have also been studying a yeast E2, U

E2 enzymes (UbcH5A-C) have been cloNed and charActerIzeD. ThEsE E2s aRe wiDely expressed iN HumaN tissues and function in cOnjunCtIOn wiTH tHe onlY characTErIZEd hUmAn e3, E6-Ap, iN ThE ubiqUitInation Of proteins. we hAvE also been stuDYiNg a novel yeAst e2, U

E2 enzymes (UbcH5A-C) hav e been clo ned a ndcha ra cter ized . These E2s ar e  wid ely expressed in human  tiss ue s  and fu nctio n in co n ju n c tio nwi thth e  o nly c har acteriz ed human E 3,E6 -AP, in theu bi quitinatio n o f proteins.Wehave a ls o b e en st udy ing a  novel yeastE2, U

E2_enzymes (UbcH5A-C)_have been cloned and_characterized. These_E2s_are widely_expressed_in human tissues_and function in_conjunction with the only_characterized human E3,_E6-AP,_in the ubiquitination of proteins. We have also been studying a novel yeast E2,_U


cell culture model of mutant SOD1-linked ALS. 4) To determine whether Bcl-2 mediates mutant SOD1 mitochondrial translocation. 5) To study the correlation between mutant SOD1/Bcl-2-containing aggregates and ALS using transgenic ALS mice and patients. In this project, the investigators propose to study the pathophysiology

cell culture model of mutant SOD1 - linked ALS. 4) To settle whether Bcl-2 intercede mutant SOD1 mitochondrial translocation. 5) To study the correlation between mutant SOD1 / Bcl-2 - containing aggregate and ALS using transgenic ALS mouse and affected role. In this project, the research worker propose to study the pathophysiology

cepl culture model of mutakt SOD1-linked ALS. 4) To devermine whether Bcl-2 mediates mutant SOD1 mitlcyondrual translocation. 5) To rtudy the correlarion vetween muvznt SOD1/Nel-2-confwiniug aggregates anc ALS usinc transgenic ANS mnce and patients. In this project, the investogwtors propose jo stldr ths pathophysiology

cell culture model of mutant SOD1-linked ALS. determine Bcl-2 mediates SOD1 mitochondrial translocation. between SOD1/Bcl-2-containing aggregates and using transgenic ALS and patients. In this project, the propose to study the pathophysiology

cell culture model of mutant SoD1-linked ALs. 4) To deTerMinE wHethEr BcL-2 mediates mutanT sOD1 mItochondrial translocatIon. 5) To StUDy thE CoRrelaTion betWEeN MUtaNt sOd1/BcL-2-cONtAininG agGregateS and ALS usiNg tRaNsgenic ALS miCE aNd patients. in tHis project, thE inVestigAtOrs PRoposE to Study The patHOphysiOlogy

cell culture model of mut ant SOD1-l inked  AL S.4)  Todete rmine whetherB cl-2  mediates mutant SOD1mitoc ho n dria l  t ransl ocation .  5 ) Tost ud y t he co rrela tio n betwe en mutantSOD 1/ Bcl-2-contai n in g aggregat esand ALS usin g t ransge ni c A L S mic e a nd pa tients .  In th is projec t, the in v estigat o r sprop ose to study thep at h ophysiology

cell_culture model_of mutant SOD1-linked ALS._4) To_determine_whether Bcl-2_mediates_mutant SOD1 mitochondrial_translocation. 5) To_study the correlation between_mutant SOD1/Bcl-2-containing aggregates_and_ALS using transgenic ALS mice and patients. In this project, the investigators propose to_study_the pathophysiology


catalyze CO/CO2 redox. Many of these developments (recombinant biosynthesis of active alpha, discovery of the tunnel and of active site coupling) arose from efforts of the previous granting period which resulted in 11 publications. The methodologies used for the project include enzyme kinetics (stopped-flow, rapid freeze-qu

catalyze CO / CO2 redox. Many of these developments (recombinant biosynthesis of active alpha, discovery of the tunnel and of active site yoke) arise from efforts of the previous granting time period which leave in 11 publications. The methodologies use for the undertaking include enzyme kinetics (stopped - flow, rapid freeze - qu

cahalyze CO/CO2 redox. Many on these developmgnrs (recmmbinaht biosyvthesis of active alpha, disclvwry od the tunnel and of acgive site couplint) ariwe from efhkrts of the pdcviouv granting peripd which rasulted in 11 putlkcctions. The methodologies used for thq projevt include enzymg kinttiss (sfopped-flow, rapid freeze-qu

catalyze CO/CO2 redox. Many of these developments of alpha, discovery the tunnel and from of the previous period which resulted 11 publications. The methodologies used for project include enzyme kinetics (stopped-flow, rapid freeze-qu

catalyze CO/CO2 redox. Many of thEse developMents (RecOmbInAnt bIosyNthesis of activE AlphA, discovery of the tunnel aNd of aCtIVe siTE cOupliNg) arose FRoM EFfoRtS oF thE pREvIous gRanTing perIod which reSulTeD in 11 publicatiONs. the methodoLogIes used for thE prOject iNcLudE EnzymE kiNeticS (stoppED-flow, rApid freezE-qU

catalyze CO/CO2 redox. Ma ny of thes e dev elo pme nt s (r ecom binant biosynt h esis  of active alpha, disc overy  o f  the tu nneland ofa ct i v e s it ecou pl i ng ) aro sefrom ef forts of t hepr evious grant i ng  period wh ich  resulted in  11  publi ca tio n s. Th e m ethod ologie s  usedfor the p ro j ect in c lude en z y me  kin etics (stopped-fl o w, rapid freeze-q u

catalyze_CO/CO2 redox._Many of these developments_(recombinant biosynthesis_of_active alpha,_discovery_of the tunnel_and of active_site coupling) arose from_efforts of the_previous_granting period which resulted in 11 publications. The methodologies used for the project include_enzyme_kinetics (stopped-flow,_rapid_freeze-qu


will be used to amplify appropriate areas of DNA. Parallel studies will be undertaken in cell lines and primary cultures of epithelial cells. Finally, the effects of retinoids and thyroid hormones on differentiating epidermis in tissue culture will be determined. Thus, our aims in the 5 years for which we are requesting support will be: 1

will be used to amplify appropriate areas of DNA. Parallel studies will be undertake in cellular telephone lines and primary acculturation of epithelial cell. Finally, the effects of retinoids and thyroid gland hormones on differentiating epidermis in tissue culture will be determine. Thus, our aims in the 5 year for which we are requesting support will be: 1

wipl be used to amplify apkropriate areas oy DNA. Perallel studies will be undertaken in cell pibes abd primary cultures of epitheliwl cells. Finelly, the effects of retikjids wnd chbroid hormones pn differettiating epidesmks in tissue culture will be determinqd. Thus, okr aims in the 5 yesws fkg chich we are requesting support will bt: 1

will be used to amplify appropriate areas Parallel will be in cell lines cells. the effects of and thyroid hormones differentiating epidermis in tissue culture will determined. Thus, our aims in the 5 years for which we are requesting will be: 1

will be used to amplify appropRiate areas Of DNA. parAllEl StudIes wIll be undertakeN In ceLl lines and primary cultuRes of EpIThelIAl Cells. finally, THe EFFecTs Of RetInOIdS and tHyrOid hormOnes on diffEreNtIating epiderMIs In tissue cuLtuRe will be deteRmiNed. ThuS, oUr aIMs in tHe 5 yEars fOr whicH We are rEquesting SuPPort wiLL be: 1

will be used to amplify a ppropriate  area s o f D NA . Pa rall el studies wil l  beundertaken in cell lin es an dp rima r ycultu res ofe pi t h eli al  c ell s. Fi nally , t he effe cts of ret ino id s and thyroi d  h ormones on  di fferentiatin g e piderm is  in tissu e c ultur e will be det ermined.Th u s, our aims in t he  5 y ears for which we ar e  requesting su pportwi l lb e : 1

will_be used_to amplify appropriate areas_of DNA._Parallel_studies will_be_undertaken in cell_lines and primary_cultures of epithelial cells._Finally, the effects_of_retinoids and thyroid hormones on differentiating epidermis in tissue culture will be determined. Thus,_our_aims in_the_5_years for which we are_requesting support will be: 1


of stored blood. This line of research has resulted in the publication of 5 papers to date. The objective of this project is to use a retrovirus-based mouse model system to understand how inappropriate activation of transcription factors in hematopoietic cells can result in the development of leukemia. We have been studying the myb-ets-

of stored blood. This line of research has resulted in the issue of 5 composition to date. The objective of this project is to practice a retrovirus - based shiner model system to sympathize how inappropriate activation of transcription factors in hematopoietic cell can result in the development of leukemia. We have been learn the myb - ets-

of stored blood. This line uf research has resultxd in tge publization of 5 papers to date. Thx obhectice of this project is go use a getroviruw-bastd mouse model system to mudersfwnd kox inappropriate activatiot of transcripdiun factors in hematopoietic cells can result ij the developmgnt og leuivmla. We have been studying the myb-sts-

of stored blood. This line of research in publication of papers to date. is use a retrovirus-based model system to how inappropriate activation of transcription factors hematopoietic cells can result in the development of leukemia. We have been studying myb-ets-

of stored blood. This line of reSearch has rEsultEd iN thE pUbliCatiOn of 5 papers to daTE. The Objective of this project Is to uSe A RetrOViRus-baSed mousE MoDEL syStEm To uNdERsTand hOw iNappropRiate activAtiOn Of transcriptIOn Factors in hEmaTopoietic celLs cAn resuLt In tHE deveLopMent oF leukeMIa. We haVe been stuDyINg the mYB-ets-

of stored blood. This lin e of resea rch h asres ul tedin t he publication of 5  papers to date. The o bject iv e  oft hi s pro ject is to u seare tro vi r us -base d m ouse mo del system  to  u nderstand ho w  i nappropria teactivation o f t ranscr ip tio n  fact ors  in h ematop o ieticcells can  r e sult i n  the de v e lo pmen t of leukemia. We ha v e been studyin g themy b -e t s -

of_stored blood._This line of research_has resulted_in_the publication_of_5 papers to_date. The objective_of this project is_to use a_retrovirus-based_mouse model system to understand how inappropriate activation of transcription factors in hematopoietic cells_can_result in_the_development_of leukemia. We have been_studying the myb-ets-


bilayer, thereby associating the protein moiety with the lipid bilayer of choice, for example, a liposome or viable cell membrane. We have demonstrated that a ganglioside conjugate with rabbit IgG can associate with human or sheep erythrocytes, since the cells may be hemagglutinated with goat anti-rabbit IgG after incubation with

bilayer, thereby associating the protein moiety with the lipid bilayer of choice, for example, a liposome or viable cellular telephone membrane. We have attest that a ganglioside conjugate with rabbit immunoglobulin g can associate with human or sheep red blood cell, since the cells may be hemagglutinated with goat anti - rabbit immunoglobulin g after incubation with

bipayer, thereby associatinn the protein monwty wivh the mipid biuayer of choice, for example, e liposomt or viable cell meobrane. We have denonsurated that a ganjmioside conjufwte civh rabbit IgG csn associade with human mr skeep erythrocytes, since the cells mar be hekahglutinated wijh gose anfp-rcbbit IgG after incubation with

bilayer, thereby associating the protein moiety with bilayer choice, for a liposome or demonstrated a ganglioside conjugate rabbit IgG can with human or sheep erythrocytes, since cells may be hemagglutinated with goat anti-rabbit IgG after incubation with

bilayer, thereby associating The protein MoietY wiTh tHe LipiD bilAyer of choice, foR ExamPle, a liposome or viable ceLl memBrANe. We HAvE demoNstrateD ThAT A gaNgLiOsiDe COnJugatE wiTh rabbiT IgG can assOciAtE with human or SHeEp erythrocYteS, since the celLs mAy be heMaGglUTinatEd wIth goAt anti-RAbbit IGG after inCuBAtion wITh

bilayer, thereby associat ing the pr otein  mo iet ywith  the  lipid bilayer of c hoice, for example, alipos om e  orv ia ble c ell mem b ra n e . W eha vede m on strat edthat agangliosid e c on jugate withr ab bit IgG ca n a ssociate wit h h uman o rshe e p ery thr ocyte s, sin c e thecells may  b e  hemag g lutinat e d  w ithgoat anti-rabbitI gG after incubati on wit h

bilayer,_thereby associating_the protein moiety with_the lipid_bilayer_of choice,_for_example, a liposome_or viable cell_membrane. We have demonstrated_that a ganglioside_conjugate_with rabbit IgG can associate with human or sheep erythrocytes, since the cells may_be_hemagglutinated with_goat_anti-rabbit_IgG after incubation with


assays for it. Such assays then will permit the specific measurement of NGF in man. More recent studies have shown that NGF can significantly promote the healing of experimentally induced wounds in animals, that it can substitute specifically for the first component of human complement, and that it is chemotactic for leukocytes. These findings indicate

assays for it. Such assays then will permit the specific measurement of NGF in man. More late cogitation have shown that NGF can importantly promote the healing of experimentally induce wounds in animal, that it can substitute specifically for the first component of human complement, and that it is chemotactic for leukocytes. These determination indicate

asswys for it. Such assays tmen will permit jhw specmfic mezsuremeng of NGF in man. More recent dtydies have shown that NGF cxn signifpcantly peomoue the healing of experimcutallg indbcxd wounds in anlmals, that ht can substitgtd dpecifically for the first componene of hukaj complement, agd tnwt if is chemotactic for leukocytes. Thsse finvings indicate

assays for it. Such assays then will specific of NGF man. More recent can promote the healing experimentally induced wounds animals, that it can substitute specifically the first component of human complement, and that it is chemotactic for leukocytes. findings indicate

assays for it. Such assays then Will permit The spEciFic MeAsurEmenT of NGF in man. MorE ReceNt studies have shown that nGF caN sIGnifICaNtly pRomote tHE hEALinG oF eXpeRiMEnTally IndUced wouNds in animaLs, tHaT it can substiTUtE specificaLly For the first cOmpOnent oF hUmaN ComplEmeNt, and That it IS chemoTactic for LeUKocyteS. these fiNDInGs inDicate

assays for it. Such assays  then will  perm itthe  s peci ficmeasurement of NGFin man. More recent st udies  h a ve s h ow n tha t NGF c a ns i gni fi ca ntl yp ro motethe  healin g of exper ime nt ally induced wo unds in an ima ls, that itcan  subst it ute speci fic allyfor th e  first  componen to f huma n  comple m e nt , an d that it is chem o ta c tic for leukoc ytes.Th e se f ind ing s indicate

assays for_it. Such_assays then will permit_the specific_measurement_of NGF_in_man. More recent_studies have shown_that NGF can significantly_promote the healing_of_experimentally induced wounds in animals, that it can substitute specifically for the first component_of_human complement,_and_that_it is chemotactic for leukocytes._These findings indicate


ade), AIDS related malignancies (Dr. Liebowitz), surgical oncology (Dr. Michelassi) and pathology (Dr. Vardiman); (4) to encourage Chicago faculty to be protocol chairs for future protocols; and (5) to actively assist and participate in the CALGB committees of audit, minority

ade), AIDS related malignancies (Dr. Liebowitz), surgical oncology (Dr. Michelassi) and pathology (Dr. Vardiman); (4) to encourage Chicago faculty to be protocol president for future protocol; and (5) to actively assist and participate in the CALGB committees of audited account, minority

ade), AIDS related malignancits (Dr. Liebowitz), sortical mncolofy (Dr. Mizhelassi) and pathology (Dr. Vacdimqn); (4) ti encourage Chicago fazulty to he protoxol rhairs for futurx protocols; ans (5) to ectively assist and partiwipate in the WAUGY committees of audit, minority

ade), AIDS related malignancies (Dr. Liebowitz), surgical Michelassi) pathology (Dr. (4) to encourage chairs future protocols; and to actively assist participate in the CALGB committees of minority

ade), AIDS related malignancieS (Dr. LiebowiTz), surGicAl oNcOlogY (Dr. MIchelassi) and paTHoloGy (Dr. Vardiman); (4) to encouragE ChicAgO FacuLTy To be pRotocol CHaIRS foR fUtUre PrOToCols; aNd (5) tO activeLy assist anD paRtIcipate in the caLgB committeEs oF audit, minoriTy

ade), AIDS related maligna ncies (Dr.  Lieb owi tz) ,surg ical  oncology (Dr. Mich elassi) and pathology(Dr.Va r dima n );  (4)to enco u ra g e  Ch ic ag o f ac u lt y tobeprotoco l chairs f orfu ture protoco l s;  and (5) t o a ctively assi stand pa rt ici p ate i n t he CA LGB co m mittee s of audi t, minori t y

ade), AIDS_related malignancies_(Dr. Liebowitz), surgical oncology_(Dr. Michelassi)_and_pathology (Dr._Vardiman);_(4) to encourage_Chicago faculty to_be protocol chairs for_future protocols; and_(5)_to actively assist and participate in the CALGB committees of audit, minority


therapy. We have previously expressed a TAT-GC fusion protein in which recombinant glucocerebrosidase (GC) is fused to 11-amino acid peptide from the HIV-1 transactivator protein (TAT) which functions to facilitate the transport of the enzyme across the plasma membrane of a variety of cell

therapy. We have previously expressed a TAT - GC fusion protein in which recombinant glucocerebrosidase (GC) is fused to 11 - amino acid peptide from the HIV-1 transactivator protein (TAT) which functions to help the ecstasy of the enzyme across the plasma membrane of a variety of cell

thfrapy. We have previously expressed a TAJ-GX fusimn profein in dhich recombinant glucocerebcosiease (TC) is fused to 11-amino azid peptife from rhe IIV-1 transactivator protelu (TAT) ahick hunctions to fagilitate tha transport of tfe enzyme across the plasma membrane jf a vatifty of cell

therapy. We have previously expressed a TAT-GC in recombinant glucocerebrosidase is fused to HIV-1 protein (TAT) which to facilitate the of the enzyme across the plasma of a variety of cell

therapy. We have previously exPressed a TAt-GC fuSioN prOtEin iN whiCh recombinant gLUcocErebrosidase (GC) is fused tO 11-aminO aCId pePTiDe froM the HIV-1 TRaNSActIvAtOr pRoTEiN (TAT) wHicH functiOns to facilItaTe The transport OF tHe enzyme acRosS the plasma meMbrAne of a VaRieTY of ceLl

therapy. We have previous ly express ed aTAT -GC  f usio n pr otein in which reco mbinant glucocerebrosi dase(G C ) is fu sed t o 11-am i no a cid  p ep tid ef ro m the  HI V-1 tra nsactivato r p ro tein (TAT) w h ic h function s t o facilitate  th e tran sp ort of th e e nzyme  acros s  the p lasma mem br a ne ofa  variet y of  cel l

therapy._We have_previously expressed a TAT-GC_fusion protein_in_which recombinant_glucocerebrosidase_(GC) is fused_to 11-amino acid_peptide from the HIV-1_transactivator protein (TAT)_which_functions to facilitate the transport of the enzyme across the plasma membrane of a_variety_of cell


in Fmr1 knockout mice that lack the Fragile X mental retardation protein (FMRP), using immunohistochemical methods. Importantly, the patterns of expression of the 12 subunit will be followed throughout early postnatal development in wild-type and Fmr1 knockout mice in order to identify early changes that could be associated with loss

in Fmr1 knockout mice that lack the Fragile X mental slowdown protein (FMRP), use immunohistochemical methods. Importantly, the patterns of expression of the 12 fractional monetary unit will be followed throughout early postnatal development in wild - character and Fmr1 smasher mice in order to identify early changes that could be associated with passing

in Fmr1 knockout mice that uack the Fragilg Z mentel retaddation orotein (FMRP), using immunohisvochwmicao methods. Importantly, ghe pattegns of expreswuon of the 12 subunib wilm be yoolowed throughput early [ostnatal devenoomznt in wild-type and Fmr1 knockout micq in orceg to identify garly shanfvs that could be associated witg loss

in Fmr1 knockout mice that lack the mental protein (FMRP), immunohistochemical methods. Importantly, the subunit will be throughout early postnatal in wild-type and Fmr1 knockout mice order to identify early changes that could be associated with loss

in Fmr1 knockout mice that lack The Fragile x mentAl rEtaRdAtioN proTein (FMRP), using iMMunoHistochemical methods. ImPortaNtLY, the PAtTerns Of expreSSiON Of tHe 12 SuBunIt WIlL be foLloWed throUghout earlY poStNatal developMEnT in wild-typE anD Fmr1 knockout MicE in ordEr To iDEntifY eaRly chAnges tHAt coulD be associAtED with lOSs

in Fmr1 knockout mice tha t lack the  Frag ile  Xme ntal  ret ardation prote i n (F MRP), using immunohist ochem ic a l me t ho ds. I mportan t ly , the  p at ter ns of  expr ess ion ofthe 12 sub uni twill be foll o we d througho utearly postna tal  devel op men t  in w ild -type  and F m r1 kno ckout mic ei n orde r  to ide n t if y ea rly changes thatc ou l d be associate d with  l o ss

in_Fmr1 knockout_mice that lack the_Fragile X_mental_retardation protein_(FMRP),_using immunohistochemical methods._Importantly, the patterns_of expression of the_12 subunit will_be_followed throughout early postnatal development in wild-type and Fmr1 knockout mice in order to_identify_early changes_that_could_be associated with loss


dysfunction (PTTD) results in a debilitating flatfoot deformity which is increasingly recognized as a major problem in the treatment of foot and ankle disorders. In fact, this disorder is felt to be the number one foot and ankle problem requiring intensive scientific investigation. The deformity is caused, at least in part

dysfunction (PTTD) results in a debilitating flatfoot deformity which is increasingly recognized as a major trouble in the discussion of metrical foot and ankle disorders. In fact, this disorderliness is felt to be the issue one foot and ankle problem necessitate intensive scientific investigation. The deformity is cause, at least in part

dydfunction (PTTD) results ik a debilitating flatfomt defkrmity wfich is increasingly recognived qs a najor problem in the tfeatment lf foot qnd enkle disorders. Mh fact, bkis djdordzr is felt to be the numbes one foot and avkpe problem requiring intensive sciegtific ongestigation. Thg defpwmitg is caused, at least in part

dysfunction (PTTD) results in a debilitating flatfoot is recognized as major problem in ankle In fact, this is felt to the number one foot and ankle requiring intensive scientific investigation. The deformity is caused, at least in part

dysfunction (PTTD) results in a DebilitatiNg flaTfoOt dEfOrmiTy whIch is increasinGLy reCognized as a major probleM in thE tREatmENt Of fooT and ankLE dISOrdErS. IN faCt, THiS disoRdeR is felt To be the numBer OnE foot and anklE PrOblem requiRinG intensive scIenTific iNvEstIGatioN. ThE defoRmity iS Caused, At least in PaRT

dysfunction (PTTD) result s in a deb ilita tin g f la tfoo t de formity whichi s in creasingly recognizedas ama j or p r ob lem i n the t r ea t m ent  o ffoo ta nd  ankl e d isorder s. In fact , t hi s disorder i s  f elt to bethe  number onefoo t andan kle probl emrequi ring i n tensiv e scienti fi c  inves t igation . Th e de formity is caused ,  a t  least in part

dysfunction_(PTTD) results_in a debilitating flatfoot_deformity which_is_increasingly recognized_as_a major problem_in the treatment_of foot and ankle_disorders. In fact,_this_disorder is felt to be the number one foot and ankle problem requiring intensive_scientific_investigation. The_deformity_is_caused, at least in part


TG-gel and CAP-DTG-NPs-Gel using female NOD SCID gamma (NSG) mice for up to 7 days. Drug dissemination will be determined using HPLC analysis to measure DTG levels in dissected tissue. We will evaluate tolerability of DTG-gel and CAP-DTG-NPs

TG - gel and CAP - DTG - NPs - Gel using female NOD SCID gamma (NSG) mice for up to 7 day. Drug dispersion will be determined using HPLC psychoanalysis to measure DTG floor in dissected tissue. We will evaluate tolerability of DTG - gel and CAP - DTG - neptunium

TG-gfl and CAP-DTG-NPs-Gel usinn female NOD SCIB gamma (NSG) mjce for jp to 7 days. Drug disseminatiln will be determined using HOLC analydis to mwasuce DTG levels in dissectcb tisame. We xill evaluate tplerabilitf of DTG-gel ang ZA'-DTG-NPs

TG-gel and CAP-DTG-NPs-Gel using female NOD SCID mice up to days. Drug dissemination analysis measure DTG levels dissected tissue. We evaluate tolerability of DTG-gel and CAP-DTG-NPs

TG-gel and CAP-DTG-NPs-Gel using Female NOD ScID gaMma (nSG) MiCe foR up tO 7 days. Drug disseMInatIon will be determined usiNg HPLc aNAlysIS tO measUre DTG lEVeLS In dIsSeCteD tISsUe. We wIll EvaluatE tolerabilIty Of dTG-gel and CAP-dtG-nPs

TG-gel and CAP-DTG-NPs-Gel  using fem ale N ODSCI Dgamm a (N SG) mice for u p  to7 days. Drug dissemina tionwi l l be de termi ned usi n gH P LCan al ysi st omeasu reDTG lev els in dis sec te d tissue. We wi ll evaluat e t olerabilityofDTG-ge land CAP-D TG- NPs

TG-gel and_CAP-DTG-NPs-Gel using_female NOD SCID gamma_(NSG) mice_for_up to_7_days. Drug dissemination_will be determined_using HPLC analysis to_measure DTG levels_in_dissected tissue. We will evaluate tolerability of DTG-gel and CAP-DTG-NPs


lines transfected with either V1a or V1b receptors showed that the pathways involved in transactivation of the MAPK pathway by VP are cell specific and independent of the V1 receptor subtype. This data suggest that VP released into the pituitary portal circulation during stress activates V1b receptor transcription through transactivation of the EGF receptor

lines transfected with either V1a or V1b receptors showed that the pathways imply in transactivation of the MAPK nerve pathway by VP are cell specific and independent of the V1 sense organ subtype. This data hint that VP released into the pituitary portal circulation during tension activate V1b receptor arrangement through transactivation of the EGF receptor

lijes transfected with eitmer V1a or V1b recgprors siowed tgat the oathways involved in transacvivarion if the MAPK pathway by VP are cvll specidic end independent of the V1 recepflr sbbvype. This data xuggest thdt VP released ivtl the pituitary portal circulation quring xtgess activates V1b geseptkg uranscription through transactivafion of the EGF receltor

lines transfected with either V1a or V1b that pathways involved transactivation of the cell and independent of V1 receptor subtype. data suggest that VP released into pituitary portal circulation during stress activates V1b receptor transcription through transactivation of the receptor

lines transfected with eitheR V1a or V1b recEptorS shOweD tHat tHe paThways involved IN traNsactivation of the MAPK pAthwaY bY vP arE CeLl speCific anD InDEPenDeNt Of tHe v1 ReCeptoR suBtype. ThIs data suggEst ThAt VP released INtO the pituitAry Portal circulAtiOn duriNg StrESs actIvaTes V1b ReceptOR transCription tHrOUgh traNSactivaTIOn Of thE EGF receptor

lines transfected with ei ther V1a o r V1b  re cep to rs s howe d that the pat h ways  involved in transacti vatio no f th e  M APK p athwayb yV P  ar ece llsp e ci fic a ndindepen dent of th e V 1receptor sub t yp e. This da tasuggest that  VP  relea se d i n to th e p ituit ary po r tal ci rculation  d u ring s t ress ac t i va tesV1b receptor tran s cr i ption throughtransa ct i va t i onofthe EGF re ce ptor

lines_transfected with_either V1a or V1b_receptors showed_that_the pathways_involved_in transactivation of_the MAPK pathway_by VP are cell_specific and independent_of_the V1 receptor subtype. This data suggest that VP released into the pituitary portal_circulation_during stress_activates_V1b_receptor transcription through transactivation of_the EGF receptor


that underlie the actions of sex steroids on differential gene transcription and translation relevat to sex differences are still not clear. Recently, we have identified splicing factor, suppressor of white-apricot homolog (Drosophila) (Sfswap), also known as splicing factor arginine/serine-rich 8, as one of

that underlie the actions of sex steroids on differential gene transcription and transformation relevat to sexual activity remainder are still not clear. Recently, we have name splicing factor, suppressor of white - apricot homolog (Drosophila) (Sfswap), besides known as splicing factor arginine / serine - fat 8, as one of

thwt underlie the actions uf sex steroids on difherentizl gene granscription and translatioi reoevat to sex differences ard still nlt clear. Rectntly, we have ideifified splicihn faccoc, suppressor of white-apriwot homolog (Drmsupkila) (Sfswap), also known as splicing fwctor atglnine/serine-ricr 8, ax one of

that underlie the actions of sex steroids gene and translation to sex differences we identified splicing factor, of white-apricot homolog (Sfswap), also known as splicing factor 8, as one of

that underlie the actions of sEx steroids On difFerEntIaL genE traNscription and tRAnslAtion relevat to sex diffeRenceS aRE stiLL nOt cleAr. RecenTLy, WE HavE iDeNtiFiED sPliciNg fActor, suPpressor of WhiTe-Apricot homolOG (DRosophila) (SFswAp), also known aS spLicing FaCtoR ArginIne/SerinE-rich 8, aS One of

that underlie the actions  of sex st eroid s o n d if fere ntia l gene transcr i ptio n and translation rele vat t os ex d i ff erenc es ares ti l l  no tcl ear .R ec ently , w e haveidentified  sp li cing factor, su ppressor o f w hite-apricot  ho molog(D ros o phila ) ( Sfswa p), al s o know n as spli ci n g fact o r argin i n e/ seri ne-rich 8, as one of

that_underlie the_actions of sex steroids_on differential_gene_transcription and_translation_relevat to sex_differences are still_not clear. Recently, we_have identified splicing_factor,_suppressor of white-apricot homolog (Drosophila) (Sfswap), also known as splicing factor arginine/serine-rich 8, as_one_of


. (Aim 2) Which rrgs are important for virulence and how do they contribute to individual RovA-associated phenotypes? (Aim 3) Are all rrgs regulated in the same way as inv? By knowing when and where these gene products are expressed combined with information regarding the phenotype of mutations

. (Aim 2) Which rrgs are important for virulence and how do they contribute to individual RovA - associated phenotypes? (Aim 3) Are all rrgs determine in the like way as inv? By knowing when and where these gene product are express combined with information see the phenotype of mutations

. (Ail 2) Which rrgs are importxnt for virulenew and iow do fhey congribute to individual RovA-asdoxiatee phenotypes? (Aim 3) Are xll rrgs gegulated in uhe same way as iib? By knowing smen aud where these ggne products are expressed cumyined with information regarding the phenotupf of mutations

. (Aim 2) Which rrgs are important and do they to individual RovA-associated rrgs in the same as inv? By when and where these gene products expressed combined with information regarding the phenotype of mutations

. (Aim 2) Which rrgs are important fOr virulencE and hOw dO thEy ContRibuTe to individual rOvA-aSsociated phenotypes? (Aim 3) are alL rRGs reGUlAted iN the samE WaY AS inV? BY kNowInG WhEn and WheRe these Gene producTs aRe Expressed comBInEd with infoRmaTion regardinG thE phenoTyPe oF MutatIonS

. (Aim 2) Which rrgs are i mportant f or vi rul enc eandhowdo they contri b uteto individual RovA-ass ociat ed phen o ty pes?(Aim 3) Ar e all  r rg s r eg u la ted i n t he same  way as in v?By  knowing whe n  a nd where t hes e gene produ cts  are e xp res s ed co mbi ned w ith in f ormati on regard in g  the p h enotype o fmuta tions

. (Aim_2) Which_rrgs are important for_virulence and_how_do they_contribute_to individual RovA-associated_phenotypes? (Aim 3)_Are all rrgs regulated_in the same_way_as inv? By knowing when and where these gene products are expressed combined with_information_regarding the_phenotype_of_mutations


transcription factor DAF-16 and extended lifespan. Conversely, preliminary analysis of a daf-2b deletion strain, generated using CRISPR, indicates that loss of daf-2b confers insulin sensitivity. Finally, using our daf-2b reporter strain, we identified specific splicing factors that alter the expression of

transcription factor DAF-16 and extended lifespan. Conversely, preliminary psychoanalysis of a daf-2b omission tenor, generated using CRISPR, indicate that loss of daf-2b confers insulin sensitivity. last, use our daf-2b reporter strain, we identify specific splicing factors that interpolate the expression of

trwnscription factor DAF-16 akd extended lifespan. Coiverselg, prelimknary analysis of a daf-2b delxtiob strqin, generated using CRKSPR, indibates thar loww of daf-2b rknfers lusulih senvmtivity. Finally, using our daf-2b reporter sgrcin, we identified specific splicing sactors tjat alter the gxprexfion of

transcription factor DAF-16 and extended lifespan. Conversely, of daf-2b deletion generated using CRISPR, confers sensitivity. Finally, using daf-2b reporter strain, identified specific splicing factors that alter expression of

transcription factor DAF-16 and Extended liFespaN. CoNveRsEly, pReliMinary analysis OF a daF-2b deletion strain, generaTed usInG cRISpr, iNdicaTes that LOsS OF daF-2b CoNfeRs INsUlin sEnsItivity. finally, usiNg oUr Daf-2b reporter STrAin, we identIfiEd specific spLicIng facToRs tHAt altEr tHe expRessioN Of

transcription factor DAF- 16 and ext ended  li fes pa n. C onve rsely, prelimi n aryanalysis of a daf-2b d eleti on stra i n,  gene rated u s in g CRI SP R,  in di c at es th atloss of  daf-2b co nfe rs  insulin sen s it ivity. Fin all y, using our  da f-2b r ep ort e r str ain , weidenti f ied sp ecific sp li c ing fa c tors th a t  a lter  the expression o f

transcription_factor DAF-16_and extended lifespan. Conversely,_preliminary analysis_of_a daf-2b_deletion_strain, generated using_CRISPR, indicates that_loss of daf-2b confers_insulin sensitivity. Finally,_using_our daf-2b reporter strain, we identified specific splicing factors that alter the expression of


understood including the important neighbor exclusion principle. Our molecular tweezers are the first bis-intercalators to force chromophores into adjacent sites. We will investigate chromophores of different "widths" to determine the origin of the neighbor exclusion principle. Those molecular tweezers which obey the principle will be unable to act

understood including the important neighbor exclusion rationale. Our molecular pincer are the beginning bis - intercalators to push chromophore into adjacent sites. We will investigate chromophores of different " width " to decide the origin of the neighbor exclusion principle. Those molecular tweezers which obey the rationale will be unable to act

unferstood including the ioportant neighbor exclnsion pdinciple. Our molecular tweezers are vhe dirst bis-intercalators to furce chrolophores inti adjacent sites. We will jkvestngete chromophorex of diffesent "widths" to ddtzrmine the origin of the neighbor exslusion pginciple. Those moltcujar fweezers which obey the principle sill be unable to acy

understood including the important neighbor exclusion principle. tweezers the first to force chromophores investigate of different "widths" determine the origin the neighbor exclusion principle. Those molecular which obey the principle will be unable to act

understood including the impOrtant neigHbor eXclUsiOn PrinCiplE. Our molecular tWEezeRs are the first bis-intercAlatoRs TO forCE cHromoPhores iNTo ADJacEnT sIteS. WE WiLl invEstIgate chRomophores Of dIfFerent "widths" TO dEtermine thE orIgin of the neiGhbOr exclUsIon PRinciPle. those MolecuLAr tweeZers which ObEY the prINciple wILL bE unaBle to act

understood including theimportantneigh bor  ex cl usio n pr inciple. Our m o lecu lar tweezers are the f irstbi s -int e rc alato rs to f o rc e chr om op hor es in to ad jac ent sit es. We wil l i nv estigate chr o mo phores ofdif ferent "widt hs"  to de te rmi n e the  or iginof the neighb or exclus io n  princ i ple. Th o s emole cular tweezers wh i ch obey the princ iple w il l  b e una ble  to act

understood_including the_important neighbor exclusion principle._Our molecular_tweezers_are the_first_bis-intercalators to force_chromophores into adjacent_sites. We will investigate_chromophores of different_"widths"_to determine the origin of the neighbor exclusion principle. Those molecular tweezers which obey_the_principle will_be_unable_to act


, no accepted sensitive and specific biological markers of total dietary fat intake for use in epidemiologic studies. Self-report measures of dietary fat may be seriously biased. By examining a combination of fatty acids, found in low concentrations, reflecting various components of a low-fat diet, it may be possible to develop a biomarker of

, no accepted sensitive and specific biological markers of total dietary adipose tissue consumption for use in epidemiologic studies. Self - report measure of dietary fat may be seriously bias. By examine a combination of fatty acids, recover in low concentrations, reflect various components of a low - adipose tissue diet, it may be possible to develop a biomarker of

, no accepted sensitive and rpecific biolognxal mackers or total aietary fat intake for use ii epudemiilogic studies. Self-repurt measuges of diwtarb fat may be sermkusly blcsed. Gn exakmning a combinajion of fattf acids, found hn llw concentrations, reflecting variouf compomejts of a low-faj dieu, ie mag be possible to develop a biomarksr of

, no accepted sensitive and specific biological total fat intake use in epidemiologic fat be seriously biased. examining a combination fatty acids, found in low concentrations, various components of a low-fat diet, it may be possible to develop a of

, no accepted sensitive and speCific bioloGical MarKerS oF totAl diEtary fat intake FOr usE in epidemiologic studieS. Self-RePOrt mEAsUres oF dietarY FaT MAy bE sErIouSlY BiAsed. BY exAmining A combinatiOn oF fAtty acids, fouND iN low concenTraTions, reflectIng VariouS cOmpONents Of a Low-faT diet, iT May be pOssible to DeVElop a bIOmarker OF

, no accepted sensitive an d specific  biol ogi cal  m arke rs o f total dietar y  fat  intake for use in epi demio lo g ic s t ud ies.Self-re p or t mea su re s o fd ie taryfat  may be  seriously  bi as ed. By exami n in g a combin ati on of fattyaci ds, fo un d i n  lowcon centr ations ,  refle cting var io u s comp o nents o f alow- fat diet, it mayb ep ossible to dev elop a  b i om a r ker  of

, no_accepted sensitive_and specific biological markers_of total_dietary_fat intake_for_use in epidemiologic_studies. Self-report measures_of dietary fat may_be seriously biased._By_examining a combination of fatty acids, found in low concentrations, reflecting various components of_a_low-fat diet,_it_may_be possible to develop a_biomarker of


, but poorly understood. Through innovative pilot studies and thoughtful planning for future studies and educational approaches we will help alleviate this alarming situation. Cystic fibrosis (CF) is characterized as a defect of electrolyte transport of epithelial cells of exocrine tissues. Central to the pathophysiology of CF is the absence of cAMP- stimulated Cl-

, but poorly understood. Through innovative pilot report and heedful planning for future studies and educational approaches we will avail facilitate this alarming situation. Cystic fibrosis (CF) is characterized as a blemish of electrolyte transport of epithelial cells of exocrine tissue. Central to the pathophysiology of CF is the absence of cAMP- stimulated Cl-

, buh poorly understood. Thromgh innovative pnoot stndies ahd thougftful planning for future stndiew and educational approacher we will help aloeviete this alarminj situatljn. Cgdtic hibrosis (CF) is gharacterizad as a defect ow zlectrolyte transport of epithelial sells og fxocrine tissugs. Cemeral no the pathophysiology of CF is the abvence of cAMP- stimulated Cl-

, but poorly understood. Through innovative pilot thoughtful for future and educational approaches alarming Cystic fibrosis (CF) characterized as a of electrolyte transport of epithelial cells exocrine tissues. Central to the pathophysiology of CF is the absence of cAMP- Cl-

, but poorly understood. ThrougH innovativE piloT stUdiEs And tHougHtful planning fOR futUre studies and educationAl appRoAChes WE wIll heLp allevIAtE THis AlArMinG sITuAtion. cysTic fibrOsis (CF) is chAraCtErized as a defECt Of electrolYte Transport of ePitHelial CeLls OF exocRinE tissUes. CenTRal to tHe pathophYsIOlogy oF cF is the ABSeNce oF cAMP- stimulated Cl-

, but poorly understood. T hrough inn ovati vepil ot  stu dies  and thoughtfu l  pla nning for future studi es an de duca t io nal a pproach e sw e  wi ll  h elp  a l le viate  th is alar ming situa tio n.  Cystic fibr o si s (CF) ischa racterized a s a  defec tofe lectr oly te tr anspor t  of ep ithelialce l ls ofe xocrine t is sues . Central to thep at h ophysiology of  CF is  t h ea b sen ceof cAMP- s ti mulat e d Cl-

, but_poorly understood._Through innovative pilot studies_and thoughtful_planning_for future_studies_and educational approaches_we will help_alleviate this alarming situation._Cystic fibrosis (CF)_is_characterized as a defect of electrolyte transport of epithelial cells of exocrine tissues. Central_to_the pathophysiology_of_CF_is the absence of cAMP-_stimulated Cl-


the same specimens originally used for RNA studies along with paired normal cells will be tested with high density 500K SNP arrays to determine if DNA and DNA + RNA signatures predict PFS. If so, clinically applicable TaqMan(r) DNA assays will be designed from SNP microarray results and tested using the same DNAs. Last,

the same specimens originally used for RNA report along with pair normal cells will be tested with high concentration 500 K SNP arrays to determine if DNA and DNA + RNA signature predict PFS. If so, clinically applicable TaqMan(r) deoxyribonucleic acid assay will be designed from SNP microarray resultant role and tested using the like DNAs. Last,

thf same specimens originauly used for RNC studixs alonf with pxired normal cells will be txstee wity high density 500K SNP afrays to feterminw if ENA and DNE + RNA slynatudcs przdmct PFS. If so, ckinically dpplicable TaqKav(r) DNA assays will be designed from SGP micrpagray results agd ttstqd uapnn the same DNAs. Last,

the same specimens originally used for RNA with normal cells be tested with to if DNA and + RNA signatures PFS. If so, clinically applicable TaqMan(r) assays will be designed from SNP microarray results and tested using the same Last,

the same specimens originallY used for RNa studIes AloNg With PairEd normal cells wILl be Tested with high density 500K sNP arRaYS to dETeRmine If DNA anD dNa + rnA sIgNaTurEs PReDict PfS. IF so, clinIcally applIcaBlE TaqMan(r) DNA aSSaYs will be deSigNed from SNP miCroArray rEsUltS And teSteD usinG the saME DNAs. LAst,

the same specimens origin ally usedfor R NAstu di es a long  with paired n o rmal  cells will be testedwithhi g h de n si ty 50 0K SNPa rr a y s t ode ter mi n eif DN A a nd DNA+ RNA sign atu re s predict PF S .If so, cli nic ally applica ble  TaqMa n( r)D NA as say s wil l be d e signed  from SNP  m i croarr a y resul t s  a nd t ested using the s a me DNAs. Last,

the_same specimens_originally used for RNA_studies along_with_paired normal_cells_will be tested_with high density_500K SNP arrays to_determine if DNA_and_DNA + RNA signatures predict PFS. If so, clinically applicable TaqMan(r) DNA assays will_be_designed from_SNP_microarray_results and tested using the_same DNAs. Last,


:B signaling could sensitize PC cells to erlotinib and gemcitabine induced killing, and (b) whether the inhibition of tumor progression could correlate with the down regulation of FoxM1/Notch-1/NF-:B signaling in animal tumor tissues. The results of our research will aid in designing

: B signaling could sensitize PC cells to erlotinib and gemcitabine induce killing, and (b) whether the prohibition of tumor progression could correlate with the down rule of FoxM1 / Notch-1 / NF-:B signaling in animal tumor tissue. The results of our research will help in designing

:B slgnaling could sensitize PC cells to erlotinib and gsmcitabive induced killing, and (b) whevher the unhibition of tumor prugression could cirreoqte with tis down vzgulaflon oy HoxM1/Notch-1/NF-:B sinnaling in dnimal tumor thsruzs. The results of our research will wid in cedigning

:B signaling could sensitize PC cells to gemcitabine killing, and whether the inhibition with down regulation of signaling in animal tissues. The results of our research aid in designing

:B signaling could sensitize Pc cells to erLotinIb aNd gEmCitaBine Induced killing, ANd (b) wHether the inhibition of tUmor pRoGRessIOn Could CorrelaTE wITH thE dOwN reGuLAtIon of foxm1/Notch-1/Nf-:B signalinG in AnImal tumor tisSUeS. The resultS of Our research wIll Aid in dEsIgnINg

:B signaling could sensiti ze PC cell s toerl oti ni b an d ge mcitabine indu c ed k illing, and (b) whethe r the  i n hibi t io n oftumor p r og r e ssi on  c oul dc or relat e w ith the  down regu lat io n of FoxM1/N o tc h-1/NF-:Bsig naling in an ima l tumo rtis s ues.The  resu lts of our re search wi ll aid in designi n g

:B signaling_could sensitize_PC cells to erlotinib_and gemcitabine_induced_killing, and_(b)_whether the inhibition_of tumor progression_could correlate with the_down regulation of_FoxM1/Notch-1/NF-:B_signaling in animal tumor tissues. The results of our research will aid in designing


frequency domain spectroscopy in providing the optical path length for photon migration in tissues is well recognized. Phase I set forth to exploit design parameters of a simplified system suitable for biomedical research and for clinical studies. Phase II will focus on construction of dual wavelength phase modulation systems that will bring to the clinic the advantages of TRs in an

frequency domain spectroscopy in providing the optical path duration for photon migration in tissue is well recognized. Phase I set forth to overwork design parameters of a simplified system desirable for biomedical inquiry and for clinical studies. Phase II will focus on construction of dual wavelength phase modulation system that will bring to the clinic the advantages of TRs in an

frfquency domain spectroscupy in providiny the o'tical lath leneth for photon migration in vissyes iw well recognized. Phasd I set flrth to wxpliut design 'zrametevf of w sik'lified system xuitable fmr biomedical serecrch and for clinical studies. Phase YI will flcus on constroctiom of slao wavelength phase modulation systemv that will bting to the clinic the advwntahes of TRs in an

frequency domain spectroscopy in providing the optical for migration in is well recognized. exploit parameters of a system suitable for research and for clinical studies. Phase will focus on construction of dual wavelength phase modulation systems that will bring the clinic the advantages of TRs in an

frequency domain spectroscoPy in providIng thE opTicAl Path LengTh for photon migRAtioN in tissues is well recognIzed. PHaSE I seT FoRth to Exploit DEsIGN paRaMeTerS oF A sImpliFieD system Suitable foR biOmEdical researCH aNd for cliniCal Studies. Phase iI wIll focUs On cONstruCtiOn of dUal wavELength Phase moduLaTIon sysTEms that WILl BrinG to the clinic the adVAnTAges of TRs in an

frequency domain spectros copy in pr ovidi ngthe  o ptic al p ath length for phot on migration in tissue s iswe l l re c og nized . Phase Is e t f or th  to  e x pl oit d esi gn para meters ofa s im plified syst e msuitable f orbiomedical r ese arch a nd  fo r  clin ica l stu dies.P hase I I will fo cu s  on co n structi o n  o f du al wavelength pha s em odulation syst ems th at wi l l  br ing  to the cl in ic th e  advant a ge s o f T R s in an

frequency_domain spectroscopy_in providing the optical_path length_for_photon migration_in_tissues is well_recognized. Phase I_set forth to exploit_design parameters of_a_simplified system suitable for biomedical research and for clinical studies. Phase II will focus_on_construction of_dual_wavelength_phase modulation systems that will_bring to the clinic the_advantages of_TRs in an