, I and II, are highly similar in amino acid composition and function, but appear to be regulated differently at the molecular level. The overall objective of this proposal is to elucidate the mechanisms regulating the expression of these two isoenzymes and to develop new approaches to the modulation the expression of the two gene products. In addition

, I and II, are highly similar in amino acid composition and function, but appear to be determine differently at the molecular degree. The overall objective of this proposal is to elucidate the mechanism regulating the expression of these two isoenzymes and to build up modern approaches to the transition the expression of the two gene products. In summation

, I wnd II, are highly similav in amino acid eimposivion ans functiun, but appear to be regulatev didferebtly at the molecular uevel. The overall objtctive of this proposal is to emmcidace the mechanismx regulatitg the expresshov lf these two isoenzymes and to devejop new aoproaches to tre mpqulafpok the expression of the two gene producus. In addition

, I and II, are highly similar acid and function, appear to be level. overall objective of proposal is to the mechanisms regulating the expression of two isoenzymes and to develop new approaches to the modulation the expression of two gene products. In addition

, I and II, are highly similar in aMino acid coMposiTioN anD fUnctIon, bUt appear to be reGUlatEd differently at the moleCular LeVEl. ThE OvErall ObjectiVE oF THis PrOpOsaL iS To EluciDatE the mecHanisms regUlaTiNg the expressIOn Of these two IsoEnzymes and to DevElop neW aPprOAches To tHe modUlatioN The expRession of ThE Two genE ProductS. iN aDditIon

, I and II, are highly sim ilar in am ino a cid  co mp osit ionand function,b ut a ppear to be regulateddiffe re n tlya tthe m olecula r  l e v el.  T he  ov er a ll  obje cti ve of t his propos alis  to elucidat e  t he mechani sms  regulatingthe  expre ss ion of th ese  twoisoenz y mes an d to deve lo p  new a p proache s to  the  modulation the e x pr e ssion of the t wo gen ep ro d u cts . I n addition

, I_and II,_are highly similar in_amino acid_composition_and function,_but_appear to be_regulated differently at_the molecular level. The_overall objective of_this_proposal is to elucidate the mechanisms regulating the expression of these two isoenzymes and_to_develop new_approaches_to_the modulation the expression of_the two gene products. In_addition


inflammation after sensitization with house dust mite antigen, a common allergic asthma model. This heightened inflammation results in greater in vivo airway reactivity. We also demonstrate that gabra4 knockout CD4+ cells express increased inflammatory cytokines compared to wild type CD4+ cells when stimulated via the T cell receptor in vitro, suggesting

inflammation after sensitization with house dust touch antigen, a coarse allergic asthma model. This heightened inflammation result in great in vivo airway reactivity. We besides demonstrate that gabra4 knockout CD4 + cells carry increased inflammatory cytokine compared to wild type CD4 + cells when provoke via the T cell receptor in vitro, suggesting

invlammation after sensitieation with house dust mmte antjgen, a cummon allergic asthma model. Vhis heigytened inflammation rerults in hreater un vmvo airway reactmbity. We also scmonscrete that gabra4 lnockout CG4+ cells expresv knereased inflammatory cytokines compawed to eipd type CD4+ celjs wnqn sfpmmlated via the T cell receptor ih vitro, suggesting

inflammation after sensitization with house dust mite common asthma model. heightened inflammation results reactivity. also demonstrate that knockout CD4+ cells increased inflammatory cytokines compared to wild CD4+ cells when stimulated via the T cell receptor in vitro, suggesting

inflammation after sensitizAtion with hOuse dUst MitE aNtigEn, a cOmmon allergic aSThma Model. This heightened infLammaTiON resULtS in grEater in VIvO AIrwAy ReActIvITy. we alsO deMonstraTe that gabrA4 knOcKout CD4+ cells eXPrEss increasEd iNflammatory cYtoKines cOmParED to wiLd tYpe CD4+ Cells wHEn stimUlated via ThE t cell rECeptor iN VItRo, suGgesting

inflammation after sensit ization wi th ho use  du st  mit e an tigen, a commo n  all ergic asthma model. Th is he ig h tene d  i nflam mationr es u l tsin  g rea te r  i n viv o a irway r eactivity.  We  a lso demonstr a te  that gabr a4knockout CD4 + c ells e xp res s  incr eas ed in flamma t ory cy tokines c om p ared t o  wild t y p eCD4+  cells when stimu l at e d via the T ce ll rec ep t or i n v itr o, suggest in g

inflammation_after sensitization_with house dust mite_antigen, a_common_allergic asthma_model._This heightened inflammation_results in greater_in vivo airway reactivity._We also demonstrate_that_gabra4 knockout CD4+ cells express increased inflammatory cytokines compared to wild type CD4+ cells_when_stimulated via_the_T_cell receptor in vitro, suggesting


Pax-2 expression in the developing kidney is repressed as the normal epithelium matures, but is detected at higher levels in the cystic epithelium of experimental animals. The proposed experiments will determine the developmental expression pattern of Pax-2 in the cpk mouse, a well-characterized model for PKD. Furthermore,

Pax-2 expression in the developing kidney is repressed as the normal epithelium matures, but is detected at eminent degree in the cystic epithelium of experimental animals. The proposed experiments will decide the developmental expression pattern of Pax-2 in the cpk mouse, a well - characterize mannequin for PKD. Furthermore,

Pad-2 expression in the deveuoping kidney is reprevsed aa the nofmal epithelium matures, but ms dwtecttb at higher levels iv the cysnic epithwliun of experimental aknmals. Bhe pxo'osed experimenjs will detesmine the devenoomzntal expression pattern of Pax-2 in tre cpk kokse, a well-charwctegised jodel for PKD. Furthermore,

Pax-2 expression in the developing kidney is the epithelium matures, is detected at epithelium experimental animals. The experiments will determine developmental expression pattern of Pax-2 in cpk mouse, a well-characterized model for PKD. Furthermore,

Pax-2 expression in the developIng kidney iS reprEssEd aS tHe noRmal Epithelium matuREs, buT is detected at higher levEls in ThE CystIC ePitheLium of eXPeRIMenTaL aNimAlS. thE propOseD experiMents will dEteRmIne the develoPMeNtal expresSioN pattern of PaX-2 in The cpk MoUse, A Well-cHarActerIzed moDEl for PkD. FurtherMoRE,

Pax-2 expression in the d evelopingkidne y i s r ep ress ed a s the normal e p ithe lium matures, but is d etect ed at h i gh er le vels in th e cys ti cepi th e li um of  ex perimen tal animal s.Th e proposed e x pe riments wi lldetermine th e d evelop me nta l  expr ess ion p attern of Pax -2 in the  c p k mous e , a wel l - ch arac terized model for PK D . Furthermore,

Pax-2_expression in_the developing kidney is_repressed as_the_normal epithelium_matures,_but is detected_at higher levels_in the cystic epithelium_of experimental animals._The_proposed experiments will determine the developmental expression pattern of Pax-2 in the cpk mouse,_a_well-characterized model_for_PKD._Furthermore,


an Executive Director, and two Assistant Directors, will comprise the Center's Leadership Group (LG), which will meet monthly to guide its administrative and scientific direction and activities. The LG will meet semi-annually with all Core Directors to discuss Core activities and plans and financial resources for implementing them, monitor Core progress in following its

an Executive Director, and two Assistant Directors, will comprise the Center's Leadership Group (LG), which will meet monthly to guide its administrative and scientific direction and bodily process. The LG will touch semi - annually with all Core Directors to discuss Core activities and design and financial resources for implement them, monitor Core progress in following its

an Executive Director, and uwo Assistant Dirgcrors, wmll comlrise thd Center's Leadership Group (LJ), whuch wull meet monthly to gukde its afministrqtivt and scientific vjrectiok and wctirivies. The LG wilk meet semh-annually with aul Core Directors to discuss Core actyvities ajd plans and fynanbiwl rssources for implementing them, monjtor Coge progress in foklowing its

an Executive Director, and two Assistant Directors, the Leadership Group which will meet and direction and activities. LG will meet with all Core Directors to discuss activities and plans and financial resources for implementing them, monitor Core progress in its

an Executive Director, and two assistant DIrectOrs, WilL cOmprIse tHe Center's LeadeRShip group (LG), which will meet moNthly To GUide ITs AdminIstratiVE aND SciEnTiFic DiREcTion aNd aCtivitiEs. The LG wilL meEt Semi-annually WItH all Core DiRecTors to discusS CoRe actiViTieS And plAns And fiNanciaL ResourCes for impLeMEnting THem, moniTOR COre pRogress in followinG ItS

an Executive Director, an d two Assi stant  Di rec to rs,will  comprise theC ente r's Leadership Group ( LG),wh i ch w i ll  meet  monthl y  t o gui de  i tsad m in istra tiv e and s cientificdir ec tion and act i vi ties. TheLGwill meet se mi- annual ly  wi t h all  Co re Di rector s  to di scuss Cor ea ctivit i es andp l an s an d financial resou r ce s  for implement ing th em ,  m o n ito r C ore progre ss  in f o llowing it s

an_Executive Director,_and two Assistant Directors,_will comprise_the_Center's Leadership_Group_(LG), which will_meet monthly to_guide its administrative and_scientific direction and_activities._The LG will meet semi-annually with all Core Directors to discuss Core activities and_plans_and financial_resources_for_implementing them, monitor Core progress_in following its


or1, a plasma membrane protein that acts as a drug pump to clear toxic substances from the yeast cytoplasm. Yor1 is a homolog of the human cystic fibrosis transmembrane conductance regulator (CFTR), defects in which cause cystic fibrosis. Deletion of a Phe residue in Yor1, equivalent to the major disease

or1, a plasma membrane protein that acts as a drug pump to clear toxic substances from the yeast cytoplasm. Yor1 is a homolog of the human cystic fibrosis transmembrane conductance governor (CFTR), defect in which cause cystic fibrosis. Deletion of a Phe remainder in Yor1, equivalent to the major disease

or1, w plasma membrane proteik that acts as a drug pnmp to dlear tobic substances from the yeasv cyroplawm. Yor1 is a homolog of the humaj cystic fibcosis transmembrehe condmetancs regbletor (CFTR), defecjs in which wause cystic fhbfodis. Deletion of a Phe residue in Yow1, equivslfnt to the majjr dpsqase

or1, a plasma membrane protein that acts drug to clear substances from the homolog the human cystic transmembrane conductance regulator defects in which cause cystic fibrosis. of a Phe residue in Yor1, equivalent to the major disease

or1, a plasma membrane protein tHat acts as a Drug pUmp To cLeAr toXic sUbstances from tHE yeaSt cytoplasm. Yor1 is a homolOg of tHe HUman CYsTic fiBrosis tRAnSMEmbRaNe ConDuCTaNce reGulAtor (CFTr), defects in WhiCh Cause cystic fIBrOsis. DeletiOn oF a Phe residue In YOr1, equiVaLenT To the MajOr disEase

or1, a plasma membrane pro tein thatactsasa d ru g pu mp t o clear toxics ubst ances from the yeast c ytopl as m . Yo r 1is ahomolog of t hehu ma n c ys t ic  fibr osi s trans membrane c ond uc tance regula t or  (CFTR), d efe cts in which  ca use cy st icf ibros is.  Dele tion o f  a Phe  residuein Yor1,e quivale n t  t o th e major disease

or1, a_plasma membrane_protein that acts as_a drug_pump_to clear_toxic_substances from the_yeast cytoplasm. Yor1_is a homolog of_the human cystic_fibrosis_transmembrane conductance regulator (CFTR), defects in which cause cystic fibrosis. Deletion of a Phe_residue_in Yor1,_equivalent_to_the major disease


we hypothesized that combinations of: a) intestinal stem cell growth factor, R-spondinl (R-spol), b) TLR ligands, and c) transplantation of bone marrow-derived endothelial progenitor cells (EPC) and mesenchymal stem cells (MSC) would restore the IR-damaged ISC niche

we hypothesized that combinations of: a) intestinal stem cell increase agent, R - spondinl (R - spol), b) TLR ligands, and c) transplant of bone marrow - derived endothelial progenitor cell (EPC) and mesenchymal bow cells (MSC) would regenerate the IR - damaged ISC niche

we hypothesized that combikations of: a) intgsrinal vtem csll growgh factor, R-spondinl (R-spol), b) VLR oiganes, and c) transplantatiun of bonv marrow-dwrivtd endothelial progenitor cells (CPC) aud mesenchymal sjem cells (MSW) would restora ghz IR-damaged ISC niche

we hypothesized that combinations of: a) intestinal growth R-spondinl (R-spol), TLR ligands, and endothelial cells (EPC) and stem cells (MSC) restore the IR-damaged ISC niche

we hypothesized that combinaTions of: a) inTestiNal SteM cEll gRowtH factor, R-spondiNL (R-spOl), b) TLR ligands, and c) transPlantAtIOn of BOnE marrOw-derivED eNDOthElIaL prOgENiTor ceLls (ePC) and mEsenchymal SteM cElls (MSC) would REsTore the IR-dAmaGed ISC niche

we hypothesized that comb inations o f: a)  in tes ti nalstem  cell growth f a ctor , R-spondinl (R-spol),  b) T LR liga n ds , and  c) tra n sp l a nta ti on  of  b o ne  marr ow- derived  endotheli alpr ogenitor cel l s(EPC) andmes enchymal ste m c ells ( MS C)w ouldres torethe IR - damage d ISC nic he

we_hypothesized that_combinations of: a) intestinal_stem cell_growth_factor, R-spondinl_(R-spol),_b) TLR ligands,_and c) transplantation_of bone marrow-derived endothelial_progenitor cells (EPC)_and_mesenchymal stem cells (MSC) would restore the IR-damaged ISC niche


lacking functional D1 or D2 dopamine receptors. This research will be done primarily in Argentina, at the Buenos Aires University School of Medicine, in collaboration with M. Gustavo Murer, as an extension of NIH grant # R01MH060131. This project on human immunogenetics of the major histocompat

lacking functional D1 or D2 dopamine receptors. This research will be do chiefly in Argentina, at the Buenos Aires University School of Medicine, in collaboration with M. Gustavo Murer, as an extension of NIH grant # R01MH060131. This undertaking on human immunogenetics of the major histocompat

lafking functional D1 or D2 aopamine receptors. Thiv resezrch wilu be done primarily in Argenvina, at tye Buenos Aires Univerrity Scholl of Meeiciie, in collaboratmkn with M. Gusfwvo Knrer, as an exteksion of NIV grant # R01MH060131. Tvir 'roject on human immunogenetics of tre majot jistocompat

lacking functional D1 or D2 dopamine receptors. will done primarily Argentina, at the Medicine, collaboration with M. Murer, as an of NIH grant # R01MH060131. This on human immunogenetics of the major histocompat

lacking functional D1 or D2 dopaMine receptOrs. ThIs rEseArCh wiLl be Done primarily iN argeNtina, at the Buenos Aires UNiverSiTY SchOOl Of MedIcine, in COlLABorAtIoN wiTh m. guStavo murEr, as an eXtension of nIH GrAnt # R01MH060131. This prOJeCt on human iMmuNogenetics of The Major hIsTocOMpat

lacking functional D1 orD2 dopamin e rec ept ors .This  res earch will bed oneprimarily in Argentina , atth e  Bue n os  Aire s Unive r si t y  Sc ho ol  of  M e di cine,  in  collab oration wi thM.  Gustavo Mur e r,  as an ext ens ion of NIH g ran t # R0 1M H06 0 131.Thi s pro ject o n  human  immunoge ne t ics of the maj o r  h isto compat

lacking_functional D1_or D2 dopamine receptors._This research_will_be done_primarily_in Argentina, at_the Buenos Aires_University School of Medicine,_in collaboration with_M._Gustavo Murer, as an extension of NIH grant # R01MH060131. This project on human_immunogenetics_of the_major_histocompat


, spherical cellular aggregates prepared from fetal mammalian central nervous systems. With these cultures we are following the development of myelin synthesis by measuring several myelin membrane specific molecules such as sulfatides, myelin basic protein and myelin associated enzymes. Preliminary studies indicate myelin synthesis does occur in these cultures and follow the same temporal

, spherical cellular aggregates prepared from fetal mammalian central skittish system. With these cultures we are follow the exploitation of myelin synthesis by measuring respective myelin membrane specific molecules such as sulfatides, myelin basic protein and myelin associated enzymes. Preliminary study indicate myelin synthesis does happen in these cultures and follow the same temporal

, spjerical cellular aggregaues prepared from fetal kammaljan centfal nervous systems. With thede cultyres we are following ghe devellpment od mytlin synthesis by measuriky sevsval mveoin membrane skecific molewules such as vuufctides, myelin basic protein and myelyn assoviwted enzymes. Ptelimpnwry anubies indicate myelin synthesis soes ocbur in these cultires and follow the same tfmpogal

, spherical cellular aggregates prepared from fetal nervous With these we are following by several myelin membrane molecules such as myelin basic protein and myelin associated Preliminary studies indicate myelin synthesis does occur in these cultures and follow the temporal

, spherical cellular aggregatEs prepared From fEtaL maMmAliaN cenTral nervous sysTEms. WIth these cultures we are fOllowInG The dEVeLopmeNt of myeLIn SYNthEsIs By mEaSUrIng seVerAl myeliN membrane sPecIfIc molecules sUCh As sulfatidEs, mYelin basic prOteIn and mYeLin ASsociAteD enzyMes. PreLIminarY studies iNdICate myELin syntHESiS doeS occur in these cultUReS And follow the saMe tempOrAL

, spherical cellular aggre gates prep aredfro m f et al m amma lian central n e rvou s systems. With thesecultu re s  wea re  foll owing t h ed e vel op me ntof my elinsyn thesisby measuri ngse veral myelin me mbrane spe cif ic molecules  su ch assu lfa t ides,  my elinbasicp rotein  and myel in associ a ted enz y m es . Pr eliminary studies in d icate myelin s ynthes is do e s  oc cur  in thesecu lture s  and fo l lo w t hes ame temporal

, spherical_cellular aggregates_prepared from fetal mammalian_central nervous_systems._With these_cultures_we are following_the development of_myelin synthesis by measuring_several myelin membrane_specific_molecules such as sulfatides, myelin basic protein and myelin associated enzymes. Preliminary studies indicate_myelin_synthesis does_occur_in_these cultures and follow the_same temporal


mimicking the normal, ultradian endogenous rhythm. Rhythmic pulsed administration of GnRH has been used successfully in the induction of ovulation in amenorrhic women, and in the induction of puberty and maintenance of sexual maturity in both males and females with hypogonadotropic hypogonadism (HH),

mimicking the normal, ultradian endogenous rhythm. Rhythmic pulsed presidency of GnRH has been use successfully in the induction of ovulation in amenorrhic women, and in the induction of puberty and alimony of sexual maturity in both male and females with hypogonadotropic hypogonadism (HH),

milicking the normal, ultraaian endogenous rhythm. Rhythjic pulsdd administration of GnRH had veen ysed successfully in tfe inductpon of ovylatmon in amenorrhir women, and in bhe iudnction of puberjy and maintanance of sexudl mcturity in both males and females wieh hypobojadotropic hypjgonsqism (HH),

mimicking the normal, ultradian endogenous rhythm. Rhythmic of has been successfully in the women, in the induction puberty and maintenance sexual maturity in both males and with hypogonadotropic hypogonadism (HH),

mimicking the normal, ultradiAn endogenoUs rhyThm. rhyThMic pUlseD administratioN Of GnrH has been used successfuLly in ThE InduCTiOn of oVulatioN In AMEnoRrHiC woMeN, AnD in thE inDuction Of puberty aNd mAiNtenance of seXUaL maturity iN boTh males and feMalEs with HyPogONadotRopIc hypOgonadISm (HH),

mimicking the normal, ult radian end ogeno usrhy th m. R hyth mic pulsed adm i nist ration of GnRH has bee n use ds ucce s sf ullyin thei nd u c tio nof  ov ul a ti on in  am enorrhi c women, a ndin  the inducti o nof puberty  an d maintenanc e o f sexu al  ma t urity  in  both  males and fe males wit hh ypogon a dotropi c hy pogo nadism (HH),

mimicking_the normal,_ultradian endogenous rhythm. Rhythmic_pulsed administration_of_GnRH has_been_used successfully in_the induction of_ovulation in amenorrhic women,_and in the_induction_of puberty and maintenance of sexual maturity in both males and females with hypogonadotropic_hypogonadism_(HH),


biology and diseases, ocular immunology and inflammation, and retinal biology and diseases. The current investigators form the nucleus of the Case Visual Sciences Research Center (VSRC), a broader group of 40 vision researchers in 19 different basic and clinical science departments at the Case Medical Center (Case Western Reserve University School of Medicine and University Hospit

biology and diseases, ocular immunology and inflammation, and retinal biology and disease. The current detective form the nucleus of the Case Visual Sciences Research Center (VSRC), a broad group of 40 imagination researchers in 19 different basic and clinical skill departments at the Case Medical Center (Case Western Reserve University School of Medicine and University Hospit

billogy and diseases, oculav immunology and inflamkation, and retknal biology and diseases. Thx cuerent investigators form thd nucleus of the Xase Cisual Scixhces Research Gentex (TSRC), a broader nroup of 40 vhsion researcharr nn 19 different basic and clinical sciqnce delagtments at the Cast Mqdiczl Center (Case Western Reserve Unibersity School of Mecicine and University Hosplt

biology and diseases, ocular immunology and inflammation, biology diseases. The investigators form the Sciences Center (VSRC), a group of 40 researchers in 19 different basic and science departments at the Case Medical Center (Case Western Reserve University School of and University Hospit

biology and diseases, ocular iMmunology aNd infLamMatIoN, and RetiNal biology and dISeasEs. The current investigatOrs foRm THe nuCLeUs of tHe Case VISuAL sciEnCeS ReSeARcH CentEr (VsRC), a broAder group oF 40 viSiOn researcherS In 19 Different bAsiC and clinical SciEnce dePaRtmENts at The case MEdical cEnter (CAse WesterN REServe UNIversitY sChOol oF Medicine and UniveRSiTY Hospit

biology and diseases, ocu lar immuno logyand  in fl amma tion , and retinalb iolo gy and diseases. The c urren ti nves t ig ators  form t h en u cle us  o f t he Ca se Vi sua l Scien ces Resear chCe nter (VSRC), abroader gr oup  of 40 visio n r esearc he rsi n 19dif feren t basi c  and c linical s ci e nce de p artment s at  the  Case Medical Cen t er (Case WesternReserv eU ni v e rsi tySchool ofMe dicin e  and Un i ve r s i tyH ospit

biology_and diseases,_ocular immunology and inflammation,_and retinal_biology_and diseases._The_current investigators form_the nucleus of_the Case Visual Sciences_Research Center (VSRC),_a_broader group of 40 vision researchers in 19 different basic and clinical science departments_at_the Case_Medical_Center_(Case Western Reserve University School_of Medicine and University Hospit


hypothesis by focusing on two aims. Aim 1: Determine effects of cocaine-induced down-regulation of anti-HIV cellular miRNAs on HIV-1 replication. Aim 2: Examine whether cocaine-induced down-regulation of anti-HIV cellular miRNAs activate latently infected HIV-1. PUBLIC HEALTH RELEVANCE:

hypothesis by focusing on two aims. Aim 1: Determine effect of cocaine - induce down - regulation of anti - HIV cellular miRNAs on HIV-1 replication. Aim 2: probe whether cocaine - induced down - regulation of anti - HIV cellular miRNAs trip latently infected HIV-1. PUBLIC HEALTH RELEVANCE:

hyoothesis by focusing on uwo aims. Aim 1: Detgrnine ehfects kf cocaive-induced down-regulation of enti-YIV ctjlular miRNAs on HKV-1 replicwtion. Ain 2: Eeamine whether cocaine-induced slwn-rzgnlation of anti-MIV cellulas miRNAs activdtd patently infected HIV-1. PUBLIC HEALTH RELEVAMCF:

hypothesis by focusing on two aims. Aim effects cocaine-induced down-regulation anti-HIV cellular miRNAs Examine cocaine-induced down-regulation of cellular miRNAs activate infected HIV-1. PUBLIC HEALTH RELEVANCE:

hypothesis by focusing on two Aims. Aim 1: DetErminE efFecTs Of coCainE-induced down-reGUlatIon of anti-HIV cellular mirNAs oN Hiv-1 repLIcAtion. aim 2: ExamINe WHEthEr CoCaiNe-INdUced dOwn-RegulatIon of anti-HiV cElLular miRNAs aCTiVate latentLy iNfected HIV-1. PUbLIc HEALTh ReLEvaNCE:

hypothesis by focusing on  two aims.  Aim1:Det er mine  eff ects of cocain e -ind uced down-regulation o f ant i- H IV c e ll ularmiRNAso nH I V-1  r ep lic at i on . Aim  2:  Examin e whethercoc ai ne-induced d o wn -regulatio n o f anti-HIV c ell ular m iR NAs activ ate  late ntly i n fected  HIV-1. P UB L IC HEA L TH RELE V A NC E:

hypothesis_by focusing_on two aims. Aim_1: Determine_effects_of cocaine-induced_down-regulation_of anti-HIV cellular_miRNAs on HIV-1_replication. Aim 2: Examine_whether cocaine-induced down-regulation_of_anti-HIV cellular miRNAs activate latently infected HIV-1. PUBLIC HEALTH RELEVANCE:


human monoclonal antibody A12. This aim will use the 27 unique human prostate cancer xenografts available in the Biospecimen Core as well as our preclinical finding of the significant synergy between castration and IGF-IR inhibition. Aim 2. Analysis of the functional interactions of the AR on IGF-IR gene expression as a

human monoclonal antibody A12. This aim will use the 27 unique human prostate gland cancer heterograft available in the Biospecimen Core equally well as our preclinical finding of the significant synergy between castration and IGF - IR prohibition. Aim 2. Analysis of the functional interaction of the AR on IGF - IR gene expression as a

hulan monoclonal antibody X12. This aim will use thx 27 uniqhe human prostate cancer xenografts evaioable in the Biospecimen Cofe as welp as our prerlinical finding of the signifjgant vbnergy between gastration dnd IGF-IR inhitigiln. Aim 2. Analysis of the functional ynteracyilns of the AR jn IBS-IR fvnt expression as a

human monoclonal antibody A12. This aim will 27 human prostate xenografts available in as preclinical finding of significant synergy between and IGF-IR inhibition. Aim 2. Analysis the functional interactions of the AR on IGF-IR gene expression as a

human monoclonal antibody A12. THis aim will Use thE 27 unIquE hUman ProsTate cancer xenoGRaftS available in the BiospecImen COrE As weLL aS our pRecliniCAl FINdiNg Of The SiGNiFicanT syNergy beTween castrAtiOn And IGF-IR inhiBItIon. Aim 2. AnalYsiS of the functiOnaL interAcTioNS of thE AR On IGF-iR gene EXpressIon as a

human monoclonal antibody  A12. This  aimwil l u se  the  27unique human p r osta te cancer xenografts a vaila bl e  int he  Bios pecimen Co r e  as  w el l a so ur  prec lin ical fi nding of t hesi gnificant sy n er gy between  ca stration and  IG F-IR i nh ibi t ion.Aim  2. A nalysi s  of th e functio na l  inter a ctionso f  t he A R on IGF-IR genee xp r ession as a

human_monoclonal antibody_A12. This aim will_use the_27_unique human_prostate_cancer xenografts available_in the Biospecimen_Core as well as_our preclinical finding_of_the significant synergy between castration and IGF-IR inhibition. Aim 2. Analysis of the functional_interactions_of the_AR_on_IGF-IR gene expression as a


Env) expressed on cell surfaces and by direct neutralization of pseudoviruses. Env-reactive clones are used to produce mAbs that will be evaluated for epitope specificity and neutralization breadth. This information will be used to test the hypothesis that neutralization breadth is determined by monoclonal or pauciclonal responses comprised of

Env) expressed on cell surfaces and by direct neutralization of pseudoviruses. Env - reactive knockoff are use to produce mAbs that will be evaluated for epitope specificity and neutralization width. This information will be used to test the guess that neutralization width is determined by monoclonal or pauciclonal responses comprised of

Env) expressed on cell surfages and by direcj beutranizatikn of psdudoviruses. Env-reactive clonxs aee ustb to produce mAbs thxt will bv evaluatwd fie epitope specificlcy ans neucrelization breadjh. This infosmation will ba jszd to test the hypothesis that neutrwlizatipn breadth is dejermimqd bg monoclonal or pauciclonal responaes comkrised of

Env) expressed on cell surfaces and by of Env-reactive clones used to produce for specificity and neutralization This information will used to test the hypothesis that breadth is determined by monoclonal or pauciclonal responses comprised of

Env) expressed on cell surfaceS and by direCt neuTraLizAtIon oF pseUdoviruses. Env-rEActiVe clones are used to produCe mAbS tHAt wiLL bE evalUated foR EpITOpe SpEcIfiCiTY aNd neuTraLizatioN breadth. ThIs iNfOrmation will BE uSed to test tHe hYpothesis thaT neUtraliZaTioN BreadTh iS deteRmined BY monocLonal or paUcIClonal REsponseS COmPrisEd of

Env) expressed on cell sur faces andby di rec t n eu tral izat ion of pseudov i ruse s. Env-reactive clones  areus e d to pr oduce  mAbs t h at w ill  b eeva lu a te d for  ep itope s pecificity  an dneutralizati o nbreadth. T his  information  wi ll beus edt o tes t t he hy pothes i s that  neutrali za t ion br e adth is d et ermi ned by monoclonal or pauciclonal re sponse sc om p r ise d o f

Env) expressed_on cell_surfaces and by direct_neutralization of_pseudoviruses._Env-reactive clones_are_used to produce_mAbs that will_be evaluated for epitope_specificity and neutralization_breadth._This information will be used to test the hypothesis that neutralization breadth is determined_by_monoclonal or_pauciclonal_responses_comprised of


the NCRR grant to the subproject or subproject staff. We will continue investigating the intercellular and intracellular signaling pathways that lead to neuronal death (or survival) following the elimination of excitatory synaptic input to the mammalian cochlear nucleus. A major initiative during the current grant period has been to use modern genetic analysis methods

the NCRR grant to the subproject or subproject staff. We will continue investigating the intercellular and intracellular signaling nerve pathway that run to neuronal end (or survival) following the elimination of excitatory synaptic remark to the mammalian cochlear nucleus. A major initiative during the current concession menstruation has been to use mod genetic analysis method acting

thf NCRR grant to the subpvoject or subprolwct steff. We sill conginue investigating the intecceloular and intracellular sigvaling panhways thqt ltad to neuronal dxzth (or survivzp) fonoowing the elikination ox excitatory sfnxpcic input to the mammalian cochlear gucleus. A major initiatyve ctrinf the current grant period has beeh to ust modern genetic amalysis methods

the NCRR grant to the subproject or We continue investigating intercellular and intracellular neuronal (or survival) following elimination of excitatory input to the mammalian cochlear nucleus. major initiative during the current grant period has been to use modern genetic methods

the NCRR grant to the subprojeCt or subproJect sTafF. We WiLl coNtinUe investigatinG The iNtercellular and intraceLlulaR sIGnalINg PathwAys that LEaD TO neUrOnAl dEaTH (oR survIvaL) followIng the elimInaTiOn of excitatoRY sYnaptic inpUt tO the mammaliaN coChlear NuCleUS. A majOr iNitiaTive duRIng the Current grAnT Period HAs been tO USe ModeRn genetic analysis MEtHOds

the NCRR grant to the sub project or  subp roj ect  s taff . We  will continue inve stigating the intercel lular  a n d in t ra cellu lar sig n al i n g p at hw ays  t h at  lead  to  neuron al death ( orsu rvival) foll o wi ng the eli min ation of exc ita tory s yn apt i c inp utto th e mamm a lian c ochlear n uc l eus. A major i n i ti ativ e during the curr e nt grant period h as bee nt ou s e m ode rn genetic  a nalys i s metho d s

the_NCRR grant_to the subproject or_subproject staff._We_will continue_investigating_the intercellular and_intracellular signaling pathways_that lead to neuronal_death (or survival)_following_the elimination of excitatory synaptic input to the mammalian cochlear nucleus. A major initiative_during_the current_grant_period_has been to use modern_genetic analysis methods


-terminal tyrosine to tubulin. Studies on chemotaxis in connective tissue-type cells have shown that fibroblasts respond to the cell binding domain of intact fibronectin and to platelet-derived growth factor; that angiogenesis factors induce endothelial cell migration, and that transformed endothelial cells respond to angiogenesis factors, platelet-derived growth factor, and

-terminal tyrosine to tubulin. Studies on chemotaxis in connective tissue - type cells have shown that fibroblast react to the cell binding knowledge domain of entire fibronectin and to platelet - derived growth gene; that angiogenesis agent induce endothelial cell migration, and that transform endothelial cells respond to angiogenesis agent, platelet - derived growth divisor, and

-terlinal tyrosine to tubulik. Studies on chemotaxis in cohnective tissue-type cells have shown tyat fubroblasts respond to ghe cell hinding eomamn of intact fibcknectin and tk placeoet-derived groeth factor; that angiogenasks factors induce endothelial cell midration, ajd that transfjrmec endknhtlial cells respond to angiogenesjs factmrs, platelet-drrived growth factor, and

-terminal tyrosine to tubulin. Studies on chemotaxis tissue-type have shown fibroblasts respond to intact and to platelet-derived factor; that angiogenesis induce endothelial cell migration, and that endothelial cells respond to angiogenesis factors, platelet-derived growth factor, and

-terminal tyrosine to tubulin. studies on cHemotAxiS in CoNnecTive Tissue-type cellS Have Shown that fibroblasts reSpond To THe ceLL bIndinG domain OF iNTAct FiBrOneCtIN aNd to pLatElet-derIved growth FacToR; that angiogeNEsIs factors iNduCe endotheliaL ceLl migrAtIon, ANd thaT trAnsfoRmed enDOtheliAl cells reSpONd to anGIogenesIS FaCtorS, platelet-derived gROwTH factor, and

-terminal tyrosine to tubu lin. Studi es on  ch emo ta xisin c onnective tiss u e-ty pe cells have shown th at fi br o blas t srespo nd to t h ec e llbi nd ing  d o ma in of  in tact fi bronectinand  t o platelet-d e ri ved growth  fa ctor; that a ngi ogenes is  fa c torsind uce e ndothe l ial ce ll migrat io n , andt hat tra n s fo rmed  endothelial cell s  r e spond to angio genesi sf ac t o rs,  pl atelet-der iv ed gr o wth fac t or , a nd

-terminal tyrosine_to tubulin._Studies on chemotaxis in_connective tissue-type_cells_have shown_that_fibroblasts respond to_the cell binding_domain of intact fibronectin_and to platelet-derived_growth_factor; that angiogenesis factors induce endothelial cell migration, and that transformed endothelial cells respond_to_angiogenesis factors,_platelet-derived_growth_factor, and


aring rats in an enriched environment renders them resistant to addiction-like behavior in models of intravenous self administration. This project will identify molecular mechanisms underlying the protective effect of environmental enrichment and strengthen our understanding of how gene transcription affects behavior. The results of this project will lay the foundation for future treatment and prevention of drug addiction in humans

aring rats in an enriched environment renders them resistant to addiction - like demeanor in mannequin of intravenous self administration. This undertaking will identify molecular mechanism underlying the protective impression of environmental enrichment and tone our understanding of how gene transcription affects behavior. The results of this undertaking will lay the foundation for future treatment and prevention of drug addiction in humans

arijg rats in an enriched ekvironment rendets them cesistaht to adaiction-like behavior in modeps of ibtravenous self adminirtration. Nhis projwct xill identify molecular mechanjdms bnverlying the prptective exfect of envirmnoeutal enrichment and strengthen our ugderstamdlng of how geng tramfcrilniin affects behavior. The resulfs of tiis project wilk lay the foundation for fkturf treatment and prfvention of drud addiction iv humans

aring rats in an enriched environment renders to behavior in of intravenous self molecular underlying the protective of environmental enrichment strengthen our understanding of how gene affects behavior. The results of this project will lay the foundation for future and prevention of drug addiction in humans

aring rats in an enriched enviRonment renDers tHem ResIsTant To adDiction-like behAVior In models of intravenous sElf adMiNIstrATiOn. ThiS projecT WiLL IdeNtIfY moLeCUlAr mecHanIsms undErlying the ProTeCtive effect oF EnVironmentaL enRichment and sTreNgthen OuR unDErstaNdiNg of hOw gene TRanscrIption affEcTS behavIOr. The reSULtS of tHis project will lay THe FOundation for fuTure trEaTMeNT And PreVention of dRuG addiCTion in hUMaNS

aring rats in an enrichedenvironmen t ren der s t he m re sist ant to addicti o n-li ke behavior in modelsof in tr a veno u sselfadminis t ra t i on.  T hi s p ro j ec t wil l i dentify  molecular  me ch anisms under l yi ng the pro tec tive effectofenviro nm ent a l enr ich mentand st r engthe n our und er s tandin g  of how g en e tr anscription affec t sb ehavior. The r esults  o f  t h i s p roj ect will l ay  thef oundati o nf o r  fu t ure treatment  and preven t ion  of dr ug  ad d iction  in h um a ns

aring rats_in an_enriched environment renders them_resistant to_addiction-like_behavior in_models_of intravenous self_administration. This project_will identify molecular mechanisms_underlying the protective_effect_of environmental enrichment and strengthen our understanding of how gene transcription affects behavior. The_results_of this_project_will_lay the foundation for future_treatment and prevention of drug_addiction in_humans


period. The integration of training in methodology and imaging applications will be enhanced by the organization of this program as two interactive tracks of approximately equal size: Methodology and Application. We expect that the majority of fellows in the Methodology track will have Ph.D. degrees, and those in the Application track, primarily M.

period. The integration of training in methodology and imaging application will be enhance by the organization of this program as two interactive lead of approximately equal size: Methodology and Application. We expect that the majority of mate in the Methodology cut will have ph academic degree, and those in the Application track, chiefly M.

pegiod. The integration of uraining in methobilogy end imafing appuications will be enhanced bb thw orgqnization of this progfam as twl interaxtivt tracks of approejmately equal dize: Nethodology anc Applicathon. We expect dhxt the majority of fellows in the Metrodologu hrack will havg Ph.D. qegrsvs, and those in the Application track, krimarily M.

period. The integration of training in methodology applications be enhanced the organization of tracks approximately equal size: and Application. We that the majority of fellows in Methodology track will have Ph.D. degrees, and those in the Application track, primarily

period. The integration of traIning in metHodolOgy And ImAginG appLications will bE EnhaNced by the organization oF this PrOGram AS tWo intEractivE TrACKs oF aPpRoxImATeLy equAl sIze: MethOdology and appLiCation. We expeCT tHat the majoRitY of fellows in The methodOlOgy TRack wIll Have PH.D. degrEEs, and tHose in the apPLicatiON track, pRIMaRily m.

period. The integration o f training  in m eth odo lo gy a nd i maging applica t ions  will be enhanced by t he or ga n izat i on  of t his pro g ra m astw oint er a ct ive t rac ks of a pproximate lyeq ual size: Me t ho dology and  Ap plication. W e e xpectth att he ma jor ity o f fell o ws inthe Metho do l ogy tr a ck will h av e Ph .D. degrees, andt ho s e in the Appli cation  t r ac k ,  pr ima rily M.

period._The integration_of training in methodology_and imaging_applications_will be_enhanced_by the organization_of this program_as two interactive tracks_of approximately equal_size:_Methodology and Application. We expect that the majority of fellows in the Methodology track_will_have Ph.D._degrees,_and_those in the Application track,_primarily M.


We have shown that NSCLC cell lines expressing oncogenic K-Ras have elevated levels of PGE2 production, mediated through induction of cPLA2 and COX-2. Blocking this pathway inhibits transformed growth in vitro and in xeno graft models, supporting a role for cPLA2 in lung cancer progression. However,

We have shown that NSCLC cell lines expressing oncogenic thousand - Ras take elevated levels of PGE2 production, mediate through induction of cPLA2 and COX-2. Blocking this nerve pathway inhibits transformed growth in vitro and in xeno bribery model, supporting a role for cPLA2 in lung cancer progression. However,

We have shown that NSCLC ctll lines expressnbg oncmgenic K-Ras haxe elevated levels of PGE2 prldyctiob, mediated through indjction of cPLA2 ane COE-2. Blocking this 'zthway luhibifd trcnwformed growth in vitro dnd in xeno grdfg lodels, supporting a role for cPLA2 ig lung vajcer progressijn. Hpreved,

We have shown that NSCLC cell lines K-Ras elevated levels PGE2 production, mediated COX-2. this pathway inhibits growth in vitro in xeno graft models, supporting a for cPLA2 in lung cancer progression. However,

We have shown that NSCLC cell lInes expresSing oNcoGenIc k-Ras Have Elevated levels OF PGE2 Production, mediated throUgh inDuCTion OF cpLA2 anD COX-2. BloCKiNG ThiS pAtHwaY iNHiBits tRanSformed Growth in viTro AnD in xeno graft MOdEls, supportIng A role for cPLA2 In lUng canCeR prOGressIon. howevEr,

We have shown that NSCLCcell lines  expr ess ing  o ncog enic  K-Ras have el e vate d levels of PGE2 produ ction ,m edia t ed  thro ugh ind u ct i o n o fcP LA2  a n dCOX-2 . B locking  this path way  i nhibits tran s fo rmed growt h i n vitro andinxeno g ra ftm odels , s uppor ting a role f or cPLA2in lung c a ncer pr o g re ssio n. However,

We_have shown_that NSCLC cell lines_expressing oncogenic_K-Ras_have elevated_levels_of PGE2 production,_mediated through induction_of cPLA2 and COX-2._Blocking this pathway_inhibits_transformed growth in vitro and in xeno graft models, supporting a role for cPLA2_in_lung cancer_progression._However,


alterations in receptors in a model of experimental cholinergic deafferentation and in cases of AD. By immunoprecipitation, the relative abundance of proteins will be determined in basal forebrain, neocortex, and hippocampus in rats. By immunocytochemistry, the proteins will be precisely localized and colocalized with cholinergic fore

alterations in receptors in a model of experimental cholinergic deafferentation and in cases of AD. By immunoprecipitation, the proportional abundance of protein will be determine in basal forebrain, neocortex, and hippocampus in rats. By immunocytochemistry, the protein will be precisely localized and colocalized with cholinergic fore

alherations in receptors ik a model of expgrumentan choljnergic aeafferentation and in cases od AD. Vy immunoprecipitation, the relanive abuneanct of proteins will be detcxmines in yawal forebrain, keocortex, atd hippocampus iv xats. By immunocytochemistry, the protqins wikl be precisely jocakyzed and colocalized with cholinergic rore

alterations in receptors in a model of deafferentation in cases AD. By immunoprecipitation, will determined in basal neocortex, and hippocampus rats. By immunocytochemistry, the proteins will precisely localized and colocalized with cholinergic fore

alterations in receptors in a Model of expErimeNtaL chOlInerGic dEafferentation ANd in Cases of AD. By immunopreciPitatIoN, The rELaTive aBundancE Of PROteInS wIll Be DEtErminEd iN basal fOrebrain, neOcoRtEx, and hippocaMPuS in rats. By iMmuNocytochemisTry, The proTeIns WIll be PreCiselY localIZed and ColocalizEd WIth choLInergic FORe

alterations in receptorsin a model  of e xpe rim en talchol inergic deaffe r enta tion and in cases of A D. By  i m muno p re cipit ation,t he r ela ti ve  ab un d an ce of  pr oteinswill be de ter mi ned in basal fo rebrain, n eoc ortex, and h ipp ocampu sinr ats.Byimmun ocytoc h emistr y, the pr ot e ins wi l l be pr e c is elylocalized and col o ca l ized with chol inergi cf or e

alterations_in receptors_in a model of_experimental cholinergic_deafferentation_and in_cases_of AD. By_immunoprecipitation, the relative_abundance of proteins will_be determined in_basal_forebrain, neocortex, and hippocampus in rats. By immunocytochemistry, the proteins will be precisely localized_and_colocalized with_cholinergic_fore


6A regulation. (3) We will delineate the epitranscriptome changes in autism brains and manifestation in patient-derived iPS cells, including an examination of epitranscriptome variation across 30 banked Autistic brain samples and testing of the impact on disruption of the readers and writers of RNA regulation (on

6A regulation. (3) We will delineate the epitranscriptome changes in autism brains and demonstration in affected role - derived iPS cells, include an examen of epitranscriptome variation across 30 banked Autistic genius sample distribution and testing of the impact on disruption of the readers and writer of RNA regulation (on

6A rfgulation. (3) We will delintate the epitranseeiptomx changss in augism brains and manifestatioi in patitut-derived iPS cells, kncluding an examunatmon of epitransccjptome ycriatjln aeriss 30 banked Aujistic brain samples and tasgiug of the impact on disruption of thq readets and writers os RNS reghlation (on

6A regulation. (3) We will delineate the in brains and in patient-derived iPS epitranscriptome across 30 banked brain samples and of the impact on disruption of readers and writers of RNA regulation (on

6A regulation. (3) We will delineatE the epitraNscriPtoMe cHaNges In auTism brains and mANifeStation in patient-deriveD iPS cElLS, incLUdIng an ExaminaTIoN OF epItRaNscRiPToMe varIatIon acroSs 30 banked AuTisTiC brain sampleS AnD testing of The Impact on disrUptIon of tHe ReaDErs anD wrIters Of RNA rEGulatiOn (on

6A regulation. (3) We will  delineate  theepi tra ns crip tome  changes in au t ismbrains and manifestati on in  p a tien t -d erive d iPS c e ll s ,  in cl ud ing  a n  e xamin ati on of e pitranscri pto me  variation a c ro ss 30 bank edAutistic bra insample sand testi ngof th e impa c t on d isruption  o f  the r e aders a n d  w rite rs of RNA regulat i on (on

6A regulation._(3) We_will delineate the epitranscriptome_changes in_autism_brains and_manifestation_in patient-derived iPS_cells, including an_examination of epitranscriptome variation_across 30 banked_Autistic_brain samples and testing of the impact on disruption of the readers and writers_of_RNA regulation_(on


unaffected. During virus replication, naturally occurring segments with sequence rearrangement are preferentially packaged over wild-type segments. The mechanism for the improved-replication phenotype is unclear, but may be connected to duplication of RNA sequences involved in packaging of the RV genome. As an extension of these observations, we used reverse genetics to engineer duplic

unaffected. During virus replication, naturally occurring segments with succession rearrangement are preferentially box over barbarian - type section. The mechanism for the better - replication phenotype is unclear, but may be connect to duplication of RNA sequences involve in packaging of the RV genome. As an extension of these observation, we used reverse genetics to mastermind duplic

unwffected. During virus reklication, naturally occucring ssgments dith sequence rearrangement ere prefeeentially packaged ovef wild-typv segmentw. Tht mechanism for tis improyzd-repmlcatimi phenotype is onclear, but kay be connectad tl duplication of RNA sequences invojved in pwckaging of thg RV bqnoms. As an extension of these observafions, wt used reverse genrtics to engineer duplic

unaffected. During virus replication, naturally occurring segments rearrangement preferentially packaged wild-type segments. The is but may be to duplication of sequences involved in packaging of the genome. As an extension of these observations, we used reverse genetics to engineer

unaffected. During virus replIcation, natUrallY ocCurRiNg seGmenTs with sequence REarrAngement are preferentiaLly paCkAGed oVEr Wild-tYpe segmENtS. tHe mEcHaNisM fOR tHe impRovEd-repliCation phenOtyPe Is unclear, but MAy Be connecteD to Duplication oF RNa sequeNcEs iNVolveD in PackaGing of THe RV geNome. As an eXtENsion oF These obSERvAtioNs, we used reverse geNEtICs to engineer duPlic

unaffected. During virusreplicatio n, na tur all yoccu rrin g segments wit h  seq uence rearrangement ar e pre fe r enti a ll y pac kaged o v er w ild -t yp e s eg m en ts. T hemechani sm for the  im pr oved-replica t io n phenotyp e i s unclear, b utmay be  c onn e ctedtodupli cation of RNA  sequence si nvolve d  in pac k a gi ng o f the RV genome.A sa n extension of  these  o b se r v ati ons , we usedre verse genetic s  t o e ngi n eer duplic

unaffected._During virus_replication, naturally occurring segments_with sequence_rearrangement_are preferentially_packaged_over wild-type segments._The mechanism for_the improved-replication phenotype is_unclear, but may_be_connected to duplication of RNA sequences involved in packaging of the RV genome. As_an_extension of_these_observations,_we used reverse genetics to_engineer duplic


hypoglycemia (including fear of severe hypoglycemia) and post-meal hyperglycemia. The latter commonly occurs in adolescents secondary to missed meal and snack insulin boluses. Both of these issues will be addressed over the five years of this grant. As over half of severe hypoglycemic events occur during sleep, we will continue our

hypoglycemia (including fear of severe hypoglycemia) and post - meal hyperglycemia. The latter commonly occur in adolescent secondary to missed meal and bite insulin boluses. Both of these offspring will be addressed over the five years of this concession. As over one-half of severe hypoglycemic events occur during sleep, we will continue our

hyooglycemia (including feav of severe hypoyoycemie) and pkst-meal fyperglycemia. The latter comlobly oxcurs in adolescents sdcondary no missed meao and snack insulin bolussd. Boch of these issugs will be agdressed over dhd yive years of this grant. As over hals of sefege hypoglycemis evtntf ocdlr during sleep, we will continus our

hypoglycemia (including fear of severe hypoglycemia) and The commonly occurs adolescents secondary to boluses. of these issues be addressed over five years of this grant. As half of severe hypoglycemic events occur during sleep, we will continue our

hypoglycemia (including fear Of severe hyPoglyCemIa) aNd Post-Meal Hyperglycemia. THE latTer commonly occurs in adoLesceNtS SecoNDaRy to mIssed meAL aND SnaCk InSulIn BOlUses. BOth Of these Issues will Be aDdRessed over thE FiVe years of tHis Grant. As over hAlf Of seveRe HypOGlyceMic EventS occur DUring sLeep, we wilL cONtinue OUr

hypoglycemia (including f ear of sev ere h ypo gly ce mia)  and  post-meal hyp e rgly cemia. The latter comm onlyoc c ursi nadole scentss ec o n dar yto  mi ss e dmealand  snackinsulin bo lus es . Both of th e se  issues wi llbe addressed  ov er the  f ive years  of  this  grant .  As ov er half o fs evereh ypoglyc e m ic  eve nts occur durings le e p, we will con tinueou r

hypoglycemia_(including fear_of severe hypoglycemia) and_post-meal hyperglycemia._The_latter commonly_occurs_in adolescents secondary_to missed meal_and snack insulin boluses._Both of these_issues_will be addressed over the five years of this grant. As over half of_severe_hypoglycemic events_occur_during_sleep, we will continue our


. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this research continues to refine and improve the methodology of diffusion tensor imaging

. The subproject and investigator (PI) may have received primary funding from another NIH generator, and therefore could be represented in other chip entries. The mental hospital listed is for the Center, which is not necessarily the initiation for the investigator. The goal of this inquiry continue to complicate and improve the methodology of diffusion tensor imaging

. Thf subproject and investinator (PI) may havg eeceivxd primzry fundkng from another NIH source, end rhus xould be represented iv other CGISP entrues. Uhe institution lmated is for tgc Cencec, which is not kecessarily the institutimn flr the investigator. The goal of thif reseatcj continues to refpnq ans improve the methodology of diffuaion teisor imaging

. The subproject and investigator (PI) may primary from another source, and thus CRISP The institution listed for the Center, is not necessarily the institution for investigator. The goal of this research continues to refine and improve the methodology diffusion tensor imaging

. The subproject and investigaTor (PI) may haVe recEivEd pRiMary FundIng from another niH soUrce, and thus could be reprEsentEd IN othER CrISP eNtries. THE iNSTitUtIoN liStED iS for tHe CEnter, whIch is not neCesSaRily the instiTUtIon for the iNveStigator. The gOal Of this ReSeaRCh conTinUes to Refine ANd imprOve the metHoDOlogy oF DiffusiON TeNsor Imaging

. The subproject and inves tigator (P I) ma y h ave  r ecei vedprimary fundin g  fro m another NIH source,and t hu s  cou l dbe re present e di n  ot he rCRI SP en tries . T he inst itution li ste dis for the C e nt er, whichisnot necessar ily  the i ns tit u tionfor  theinvest i gator.  The goal  o f  thisr esearch c on tinu es to refine andi mp r ove the method ologyof di f f usi ontensor ima gi ng

. The_subproject and_investigator (PI) may have_received primary_funding_from another_NIH_source, and thus_could be represented_in other CRISP entries._The institution listed_is_for the Center, which is not necessarily the institution for the investigator. The goal_of_this research_continues_to_refine and improve the methodology_of diffusion tensor imaging


mature derivatives. If similar mechanisms are relevant for the cancer stem cell (CSC) model, then epigenetic modulation might enrich the CSC population, thereby facilitating CSC isolation and rigorous evaluation. To test this hypothesis, primary human cancer cells and liver cancer cell lines were treated with zebularine (ZEB), a

mature derivatives. If similar mechanisms are relevant for the cancer shank cellular telephone (CSC) model, then epigenetic modulation might enrich the CSC population, thereby facilitate CSC isolation and rigorous evaluation. To quiz this hypothesis, primary human cancer cell and liver cancer cellular telephone lines were treated with zebularine (ZEB), a

mahure derivatives. If simiuar mechanisms cee relxvant fkr the cxncer stem cell (CSC) model, thxn epigentnic modulation might dnrich thv CSC popylatmon, thereby facilitating CSC iallatnoi and rigorous gvaluation. Tm test this hy[oghzsis, primary human cancer cells and jiver csnfer cell lines wert tweatsd with zebularine (ZEB), a

mature derivatives. If similar mechanisms are relevant cancer cell (CSC) then epigenetic modulation thereby CSC isolation and evaluation. To test hypothesis, primary human cancer cells and cancer cell lines were treated with zebularine (ZEB), a

mature derivatives. If similaR mechanismS are rEleVanT fOr thE canCer stem cell (CSC) MOdel, Then epigenetic modulatiOn migHt ENricH ThE CSC pOpulatiON, tHERebY fAcIliTaTInG CSC iSolAtion anD rigorous eValUaTion. To test thIS hYpothesis, pRimAry human cancEr cElls anD lIveR CanceR ceLl linEs were TReated With zebulArINe (ZEB), a

mature derivatives. If si milar mech anism s a rere leva nt f or the cancers temcell (CSC) model, then  epig en e ticm od ulati on migh t  e n r ich  t he  CS Cp op ulati on,  thereb y facilita tin gCSC isolatio n  a nd rigorou s e valuation. T o t est th is  hy p othes is,  prim ary hu m an can cer cells  a n d live r  cancer c el l li nes were treatedw it h  zebularine (Z EB), a

mature_derivatives. If_similar mechanisms are relevant_for the_cancer_stem cell_(CSC)_model, then epigenetic_modulation might enrich_the CSC population, thereby_facilitating CSC isolation_and_rigorous evaluation. To test this hypothesis, primary human cancer cells and liver cancer cell_lines_were treated_with_zebularine_(ZEB), a


the yeast mating pathway and screen these for memory behavior. 2) Develop a screen for a complex dynamic behavior-sensory adaptation. A recombination-based FACS assay will be developed to screen for cells that can transiently respond to a stimulus, but then automatically reset output despite sustained stimulus. Comparison of functional circuit architectures is expected

the yeast mating pathway and screen these for memory behavior. 2) originate a sieve for a complex dynamic behavior - sensory adaptation. A recombination - base FACS assay will be developed to shield for cell that can transiently respond to a stimulation, but then mechanically reset output despite free burning stimulus. Comparison of functional circumference architecture is expected

thf yeast mating pathway akd screen these yir memmry begavior. 2) Aevelop a screen for a complxx dtnamix behavior-sensory adapgation. A gecombinarion-uased FACS assay will be develkied tm screen for cekls that cdn transiently rds'ond to a stimulus, but then automatisally rrsft output despyte xtstajned stimulus. Comparison of functiknal cigcuit architecturrs is expected

the yeast mating pathway and screen these behavior. Develop a for a complex FACS will be developed screen for cells can transiently respond to a stimulus, then automatically reset output despite sustained stimulus. Comparison of functional circuit architectures is

the yeast mating pathway and sCreen these For meMorY beHaVior. 2) deveLop a screen for a COmplEx dynamic behavior-sensoRy adaPtATion. a ReCombiNation-bASeD faCS AsSaY wiLl BE dEveloPed To screeN for cells tHat CaN transiently REsPond to a stiMulUs, but then autOmaTicallY rEseT OutpuT deSpite SustaiNEd stimUlus. CompaRiSOn of fuNCtional CIRcUit aRchitectures is expECtED

the yeast mating pathwayand screen  thes e f orme mory  beh avior. 2) Deve l op a  screen for a complexdynam ic beha v io r-sen sory ad a pt a t ion .Arec om b in ation -ba sed FAC S assay wi llbe  developed t o  s creen forcel ls that cantra nsient ly  re s pondtoa sti mulus, but th en automa ti c ally r e set out p u tdesp ite sustained sti m ul u s. Comparisonof fun ct i on a l  ci rcu it archite ct uresi s expec t ed

the_yeast mating_pathway and screen these_for memory_behavior._2) Develop_a_screen for a_complex dynamic behavior-sensory_adaptation. A recombination-based FACS_assay will be_developed_to screen for cells that can transiently respond to a stimulus, but then automatically_reset_output despite_sustained_stimulus._Comparison of functional circuit architectures_is expected


method to monitor surface membrane fusion events, and (3) high resolution capacitance measurements in on-cell patch clamp configuration. Preliminary Data suggests that PKC's may activate PI4K2alpha on internal membranes, thereby initiating movement of vesicles containing lipid phosphatases to the sarcolemma. Insertion at the sarcolemma appears

method to monitor surface membrane fusion events, and (3) eminent settlement capacitance measurements in on - cell plot clamp configuration. Preliminary Data suggests that PKC's may trip PI4K2alpha on internal membranes, thereby initiating motion of vesicles containing lipid phosphatase to the sarcolemma. Insertion at the sarcolemma appears

mehhod to monitor surface oembrane fusion events, and (3) gigh resulution capacitance measuremxnts in ob-cell patch clamp confkguration. Prelimibary Eata suggests that PKC's jwy aetmvate PI4K2alpha pn internan membranes, thardbv initiating movement of vesicles cogtaininb pipid phosphatwses eo tgv warcolemma. Insertion at the szrcolemka appears

method to monitor surface membrane fusion events, high capacitance measurements on-cell patch clamp PKC's activate PI4K2alpha on membranes, thereby initiating of vesicles containing lipid phosphatases to sarcolemma. Insertion at the sarcolemma appears

method to monitor surface memBrane fusioN evenTs, aNd (3) hIgH resOlutIon capacitance MEasuRements in on-cell patch clAmp coNfIGuraTIoN. PrelIminary dAtA SUggEsTs ThaT Pkc's May acTivAte PI4K2aLpha on inteRnaL mEmbranes, therEBy Initiating MovEment of vesicLes ContaiNiNg lIPid phOspHatasEs to thE SarcolEmma. InserTiON at the SArcolemMA ApPearS

method to monitor surface  membranefusio n e ven ts , an d (3 ) high resolut i on c apacitance measurement s inon - cell pa tch c lamp co n fi g u rat io n.  Pr el i mi naryDat a sugge sts that P KC' smay activate PI 4K2alpha o n i nternal memb ran es, th er eby initi ati ng mo vement of ves icles con ta i ning l i pid pho s p ha tase s to the sarcolem m a. Insertion at t he sar co l em m a  ap pea rs

method_to monitor_surface membrane fusion events,_and (3)_high_resolution capacitance_measurements_in on-cell patch_clamp configuration. Preliminary_Data suggests that PKC's_may activate PI4K2alpha_on_internal membranes, thereby initiating movement of vesicles containing lipid phosphatases to the sarcolemma. Insertion_at_the sarcolemma_appears


disrupts the normal development of the immune system, resulting in immune disfunction that may persist well into adult life. Data also indicate that stress can have a profound negative impact on immunocompetence. The proposed research is the first to investigate the interactive effects of prenatal ethanol and postweaning stress on immunocompetence

disrupts the normal development of the immune system, resulting in immune dysfunction that may prevail well into adult life. Data besides indicate that tension can have a profound minus shock on immunocompetence. The proposed inquiry is the inaugural to investigate the interactive effect of prenatal ethanol and postweaning stress on immunocompetence

didrupts the normal develokment of the immuuw systxm, resumting in immune disfunction that may pwrsisu well into adult lkfe. Data wlso inducatt that stress can have a ixofouhf neyavive impact on lmmunocompedence. The propmsdd research is the first to investigaee the onheractive effests ps prsnatal ethanol and postweaning strsss on pmmunocompetence

disrupts the normal development of the immune in disfunction that persist well into that can have a negative impact on The proposed research is the first investigate the interactive effects of prenatal ethanol and postweaning stress on immunocompetence

disrupts the normal developmEnt of the imMune sYstEm, rEsUltiNg in Immune disfunctIOn thAt may persist well into adUlt liFe. dAta aLSo IndicAte that STrESS caN hAvE a pRoFOuNd negAtiVe impacT on immunocOmpEtEnce. The propoSEd Research is The First to invesTigAte the InTerACtive EffEcts oF prenaTAl ethaNol and posTwEAning sTRess on iMMUnOcomPetence

disrupts the normal devel opment ofthe i mmu nesy stem , re sulting in imm u ne d isfunction that may pe rsist  w e ll i n to  adul t life. Da t a  al so  i ndi ca t ethatstr ess can  have a pr ofo un d negative i m pa ct on immu noc ompetence. T hepropos ed  re s earch  is  thefirstt o inve stigate t he intera c tive ef f e ct s of  prenatal ethanol an d  postweaning s tresson im m u noc omp etence

disrupts_the normal_development of the immune_system, resulting_in_immune disfunction_that_may persist well_into adult life._Data also indicate that_stress can have_a_profound negative impact on immunocompetence. The proposed research is the first to investigate the_interactive_effects of_prenatal_ethanol_and postweaning stress on immunocompetence


5-FU dermally should be more effective than 5-FU in treating BCC, AK and psoriasis while reducing the risk of systemic side effects. The goal of this proposal is to understand how developmental mechanisms contribute to neural circuits controlling animal behaviors. The simple neuroanatomy and repertoire of stereotyped locomotor behaviors of larval

5 - FU dermally should be more effective than 5 - FU in treating BCC, AK and psoriasis while reducing the risk of systemic side effect. The finish of this proposal is to understand how developmental mechanism put up to neural circuits manipulate animal behavior. The simple neuroanatomy and repertory of stereotyped locomotor demeanor of larval

5-FU dermally should be more effective than 5-FU in vreatinf BCC, AK and psoriasis while reducinj thw risj of systemic side effdcts. The hoal of rhis proposal is to undcxstans how vevelopmental mgchanisms cottribute to negrxl circuits controlling animal behavijrs. The slmple neuroanajomy sgd rsievtoire of stereotyped locomotor gehaviogs of larval

5-FU dermally should be more effective than treating AK and while reducing the The of this proposal to understand how mechanisms contribute to neural circuits controlling behaviors. The simple neuroanatomy and repertoire of stereotyped locomotor behaviors of larval

5-FU dermally should be more effEctive than 5-fU in tReaTinG BcC, AK And pSoriasis while rEDuciNg the risk of systemic sidE effeCtS. the gOAl Of thiS proposAL iS TO unDeRsTanD hOW dEveloPmeNtal mecHanisms conTriBuTe to neural ciRCuIts controlLinG animal behavIorS. The siMpLe nEUroanAtoMy and RepertOIre of sTereotypeD lOComotoR BehavioRS Of LarvAl

5-FU dermally should be m ore effect ive t han  5- FU  intrea ting BCC, AK a n d ps oriasis while reducing  theri s k of sy stemi c sidee ff e c ts.  T he  go al of  this  pr oposalis to unde rst an d how develo p me ntal mecha nis ms contribut e t o neur al  ci r cuits  co ntrol ling a n imal b ehaviors.  T h e simp l e neuro a n at omyand repertoire of st e reotyped locom otor b eh a vi o r s o f l arval

5-FU_dermally should_be more effective than_5-FU in_treating_BCC, AK_and_psoriasis while reducing_the risk of_systemic side effects. The_goal of this_proposal_is to understand how developmental mechanisms contribute to neural circuits controlling animal behaviors. The_simple_neuroanatomy and_repertoire_of_stereotyped locomotor behaviors of larval


recent studies showing spouses may be at increased risk for developing diabetes themselves because of the marital context and shared environment. PUBLIC HEALTH RELEVANCE Concerns about obesity and physical inactivity and their links to diabetes have led to public health mandates- such as those included in Healthy People 2010-aimed at reversing those trends

recent studies showing spouses may be at increase hazard for developing diabetes themselves because of the marital context and shared environment. PUBLIC HEALTH RELEVANCE Concerns about fleshiness and physical inactiveness and their links to diabetes have led to public health mandates- such as those include in Healthy People 2010 - aimed at reversing those tendency

refent studies showing spomses may be at iuxreasev risk ror deveuoping diabetes themselves bxcauwe of the marital context avd shared environnent. PUBLIC HEALTH RELEYCNCE Dlncexnw about obesiti and physicdl inactivity dna cheir links to diabetes have led to [ublic newlth mandates- fuch ws tgose included in Healthy People 2010-aijed at geversing those ttends

recent studies showing spouses may be at for diabetes themselves of the marital HEALTH Concerns about obesity physical inactivity and links to diabetes have led to health mandates- such as those included in Healthy People 2010-aimed at reversing those

recent studies showing spousEs may be at iNcreaSed RisK fOr deVeloPing diabetes thEMselVes because of the marital ConteXt ANd shAReD enviRonment. puBlic HEaLtH rELeVanCe ConcErnS about oBesity and pHysIcAl inactivity ANd Their links To dIabetes have lEd tO publiC hEalTH mandAteS- such As thosE IncludEd in HealtHy pEople 2010-aIMed at reVERsIng tHose trends

recent studies showing sp ouses maybe at  in cre as ed r iskfor developing diab etes themselves becaus e ofth e  mar i ta l con text an d  s h a red  e nv iro nm e nt . PUB LIC  HEALTH  RELEVANCE  Co nc erns about o b es ity and ph ysi cal inactivi tyand th ei r l i nks t o d iabet es hav e  led t o publiche a lth ma n dates-s u ch  asthose included in He a lthy People 20 10-aim ed at r eve rsi ng those t re nds

recent_studies showing_spouses may be at_increased risk_for_developing diabetes_themselves_because of the_marital context and_shared environment. PUBLIC HEALTH_RELEVANCE Concerns about_obesity_and physical inactivity and their links to diabetes have led to public health mandates-_such_as those_included_in_Healthy People 2010-aimed at reversing_those trends


this proposal we aim to further the development of novel and safe oral inhibitors of sEH for the treatment of peripheral neuropathy in diabetic patients. Preclinical studies with our candidate EC5026 demonstrated efficacy for diabetic neuropathy. EicOsis has selected EC5026 for its efficacy with good PK/ADME properties and stability to

this proposal we aim to further the development of fresh and dependable oral inhibitor of sEH for the treatment of peripheral neuropathy in diabetic patients. Preclinical studies with our campaigner EC5026 demonstrated efficacy for diabetic neuropathy. EicOsis has selected EC5026 for its efficacy with good PK / ADME property and stability to

thls proposal we aim to fuvther the develokmwnt of novel and safd oral inhibitors of sEH for tye trtctment of peripheral neuropatjy in diqbetmc patients. Preclinical studiea witk iur candidate GC5026 demonstraded efficacy fmr dnabetic neuropathy. EicOsis has seleceed EC5026 gog its efficacy witn goos PK/ADME properties and stability fo

this proposal we aim to further the novel safe oral of sEH for in patients. Preclinical studies our candidate EC5026 efficacy for diabetic neuropathy. EicOsis has EC5026 for its efficacy with good PK/ADME properties and stability to

this proposal we aim to furtheR the develoPment Of nOveL aNd saFe orAl inhibitors of SeH foR the treatment of peripheRal neUrOPathY In DiabeTic patiENtS. pRecLiNiCal StUDiEs witH ouR candidAte EC5026 demonStrAtEd efficacy foR DiAbetic neurOpaThy. EicOsis haS seLected eC5026 For ITs effIcaCy witH good Pk/aDME prOperties aNd STabiliTY to

this proposal we aim to f urther the  deve lop men tof n ovel  and safe oral inhi bitors of sEH for thetreat me n t of pe riphe ral neu r op a t hyin  d iab et i cpatie nts . Precl inical stu die swith our can d id ate EC5026  de monstrated e ffi cacy f or  di a betic  ne uropa thy. E i cOsishas selec te d  EC502 6  for it s ef fica cy with good PK/A D ME properties and  stabi li t yt o

this_proposal we_aim to further the_development of_novel_and safe_oral_inhibitors of sEH_for the treatment_of peripheral neuropathy in_diabetic patients. Preclinical_studies_with our candidate EC5026 demonstrated efficacy for diabetic neuropathy. EicOsis has selected EC5026 for_its_efficacy with_good_PK/ADME_properties and stability to


We have also determined that at late stages of the PMN transepithelial migration response there are binding interactions between PMN and the apical epithelial membrane mediated by specific glycan epitopes displayed on the transmembrane protein CD44v6. Such binding interactions result in epithelial functional responses that positively regulate epithelial barrier function. Details of the

We have also determined that at late stages of the PMN transepithelial migration reception there be binding interactions between PMN and the apical epithelial membrane mediated by specific glycan antigenic determinant displayed on the transmembrane protein CD44v6. Such binding interactions leave in epithelial running responses that positively regulate epithelial barrier function. Details of the

We have also determined thxt at late staggs of thx PMN tdansepitfelial migration response thxre qre bunding interactions begween PMN and the apiral epithelial mxjbrane mediatsf by wpecific glycak epitopes gisplayed on tve txansmembrane protein CD44v6. Such bindind interschions result ig epptrelizl functional responses that positjvely rtgulate epithelial barrier function. Details lf tje

We have also determined that at late the transepithelial migration there are binding apical membrane mediated by glycan epitopes displayed the transmembrane protein CD44v6. Such binding result in epithelial functional responses that positively regulate epithelial barrier function. Details of

We have also determined that aT late stageS of thE PMn trAnSepiThelIal migration reSPonsE there are binding interaCtionS bETweeN pMn and tHe apicaL EpITHelIaL mEmbRaNE mEdiatEd bY specifIc glycan epItoPeS displayed on THe TransmembrAne Protein CD44v6. SuCh bInding InTerACtionS reSult iN epithELial fuNctional rEsPOnses tHAt positIVElY regUlate epithelial baRRiER function. DetaiLs of thE

We have also determined t hat at lat e sta ges  of  t he P MN t ransepithelial migr ation response there a re bi nd i ng i n te racti ons bet w ee n PMN  a nd  th ea pi cal e pit helialmembrane m edi at ed by specif i cglycan epi top es displayed  on  the t ra nsm e mbran e p rotei n CD44 v 6. Suc h binding  i n teract i ons res u l tin e pithelial functio n al responses that  posit iv e ly r egu lat e epitheli al  barr i er func t io n . Det a ils of the

We_have also_determined that at late_stages of_the_PMN transepithelial_migration_response there are_binding interactions between_PMN and the apical_epithelial membrane mediated_by_specific glycan epitopes displayed on the transmembrane protein CD44v6. Such binding interactions result in_epithelial_functional responses_that_positively_regulate epithelial barrier function. Details_of the


of-function mutations in a gene coding for?-sarcoglycan (?-SG; gene name: SGCE in human and Sgce in mouse). SGCE is widely expressed in embryonic development and in adults. SGCE is expressed in almost all brain regions tested. We have established a Sgce

of - function mutations in a gene coding for?-sarcoglycan (? -SG; gene name: SGCE in human and Sgce in mouse). SGCE is widely carry in embryonic growth and in adults. SGCE is expressed in almost all genius regions tested. We have lay down a Sgce

of-fknction mutations in a gtne coding for?-sareiglycai (?-SG; gehe name: RGCE in human and Sgce in monse). WGCE us widely expressed in embryonib developnent qnd in adults. SGCE is exlvesseb mn almost all btain regions tested. We hava dscablished a Sgce

of-function mutations in a gene coding for?-sarcoglycan name: in human Sgce in mouse). embryonic and in adults. is expressed in all brain regions tested. We have a Sgce

of-function mutations in a genE coding for?-SarcoGlyCan (?-sG; Gene Name: sGCE in human and sGce iN mouse). SGCE is widely exprEssed In EMbryONiC deveLopment ANd IN AduLtS. SgCE Is EXpResseD in Almost aLl brain regIonS tEsted. We have eSTaBlished a SgCe

of-function mutations in a  gene codi ng fo r?- sar co glyc an ( ?-SG; gene nam e : SG CE in human and Sgce i n mou se ) . SG C Eis wi dely ex p re s s edin  e mbr yo n ic  deve lop ment an d in adult s.SG CE is expres s ed  in almost  al l brain regi ons  teste d.  We haveest ablis hed aS gce

of-function mutations_in a_gene coding for?-sarcoglycan (?-SG;_gene name:_SGCE_in human_and_Sgce in mouse)._SGCE is widely_expressed in embryonic development_and in adults._SGCE_is expressed in almost all brain regions tested. We have established a Sgce


. Half are also randomly allocated to receive 3 zoledronic acid infusions, one every 6 months. Bone mineral density and serologic markers of bone metabolism are the primary study endpoints. GOG-199 participants who cross-over from screening to surgery remain eligible for this study. The entry criteria have been relaxed to

. Half are also randomly allocated to receive 3 zoledronic acid infusion, one every 6 calendar month. Bone mineral density and serologic markers of bone metabolism are the elementary study endpoints. GOG-199 player who crossbreed - over from screen to surgery remain eligible for this study. The entrance criteria have been relaxed to

. Hapf are also randomly allucated to receirw 3 zolxdronic acid inwusions, one every 6 months. Boie munerao density and serologiz markers of bone metebolism are the 'dimary study skdpoiutw. GOG-199 participsnts who csoss-over from vcfezning to surgery remain eligible for this syufy. The entry ctiterpa havs been relaxed to

. Half are also randomly allocated to zoledronic infusions, one 6 months. Bone of metabolism are the study endpoints. GOG-199 who cross-over from screening to surgery eligible for this study. The entry criteria have been relaxed to

. Half are also randomly allocaTed to receiVe 3 zolEdrOniC aCid iNfusIons, one every 6 moNThs. BOne mineral density and seRologIc MArkeRS oF bone MetabolISm ARE thE pRiMarY sTUdY endpOinTs. GOG-199 paRticipants Who CrOss-over from sCReEning to surGerY remain eligiBle For thiS sTudY. the enTry CriteRia havE Been reLaxed to

. Half are also randomly a llocated t o rec eiv e 3  z oled roni c acid infusio n s, o ne every 6 months. Bon e min er a l de n si ty an d serol o gi c mar ke rs  of  b o ne  meta bol ism are  the prima ryst udy endpoint s .GOG-199 pa rti cipants whocro ss-ove rfro m  scre eni ng to  surge r y rema in eligib le for th i s study . Th e en try criteria have be e n relaxed to

. Half_are also_randomly allocated to receive_3 zoledronic_acid_infusions, one_every_6 months. Bone_mineral density and_serologic markers of bone_metabolism are the_primary_study endpoints. GOG-199 participants who cross-over from screening to surgery remain eligible for this_study._The entry_criteria_have_been relaxed to


(AHH) to probe the multiplicity, diversity, and different catalytic properties of the cytochromes P-450. Seven,8-benzoflavone and L-maackiain acetate are inhibitors that are effective against different forms of AHH. We are using these inhibitors to probe the active catalytic sites

(AHH) to probe the multiplicity, diversity, and different catalytic properties of the cytochrome P-450. Seven,8 - benzoflavone and L - maackiain acetate rayon are inhibitor that are effective against different forms of AHH. We are using these inhibitor to probe the active catalytic sites

(AHJ) to probe the multipliclty, diversity, anb diffecent cafalytic oroperties of the cytochromed P-450. Sevtu,8-benzoflavone and L-mxackiain wcetate qre mnhibitors that ede effegcive znainsc vifferent forms of AHH. We are using theve iuhibitors to probe the active catalyeic sitrs

(AHH) to probe the multiplicity, diversity, and properties the cytochromes Seven,8-benzoflavone and L-maackiain effective different forms of We are using inhibitors to probe the active catalytic

(AHH) to probe the multiplicity, Diversity, aNd difFerEnt CaTalyTic pRoperties of the CYtocHromes P-450. Seven,8-benzoflavoNe and l-mAAckiAIn AcetaTe are inHIbITOrs ThAt Are EfFEcTive aGaiNst diffErent forms Of AhH. we are using thESe Inhibitors To pRobe the activE caTalytiC sIteS

(AHH) to probe the multip licity, di versi ty,  an ddiff eren t catalytic pr o pert ies of the cytochromes  P-45 0. Seve n ,8 -benz oflavon e  a n d  L- ma ac kia in ac etate  ar e inhib itors that  ar eeffective ag a in st differe ntforms of AHH . W e areus ing these  in hibit ors to probethe activ ec atalyt i c sites

(AHH)_to probe_the multiplicity, diversity, and_different catalytic_properties_of the_cytochromes_P-450. Seven,8-benzoflavone and_L-maackiain acetate are_inhibitors that are effective_against different forms_of_AHH. We are using these inhibitors to probe the active catalytic sites


and have pioneered the treatment of children and pregnant women with HIV infection through both Phase I and Phase II/III trials. Over 90% of the women and children recruited into treatment protocols have been members of minority groups. The extensive infrastructure of social and medical services available at the medical center has facilitated the conduct of trials.

and have pioneered the treatment of children and pregnant charwoman with HIV contagion through both Phase I and Phase II / III trials. Over 90% of the women and child recruit into treatment protocols have been member of minority group. The extensive infrastructure of social and medical services available at the medical plaza has facilitated the conduct of trial.

anf have pioneered the trextment of childteb and 'regnanf women dith HIV infection through blty Phawe I and Phase II/III tfials. Oveg 90% of the womtn and children rxdruited into fveatmznv protocols havg been membess of minority gfobps. The extensive infrastructure of focial snf medical servyces wvaimable at the medical center has fadilitattd the conduct of yrials.

and have pioneered the treatment of children women HIV infection both Phase I 90% the women and recruited into treatment have been members of minority groups. extensive infrastructure of social and medical services available at the medical center has the conduct of trials.

and have pioneered the treatmEnt of childRen anD prEgnAnT womEn wiTh HIV infection THrouGh both Phase I and Phase II/iII trIaLS. OveR 90% Of The woMen and cHIlDREn rEcRuIteD iNTo TreatMenT protocOls have beeN meMbErs of minoritY GrOups. The extEnsIve infrastruCtuRe of soCiAl aND mediCal ServiCes avaILable aT the medicAl CEnter hAS faciliTATeD the Conduct of trials.

and have pioneered the tr eatment of  chil dre n a nd  pre gnan t women with H I V in fection through both P haseIa nd P h as e II/ III tri a ls . Ove r90 % o ft he  wome n a nd chil dren recru ite dinto treatme n tprotocolshav e been membe rsof min or ity group s.The e xtensi v e infr astructur eo f soci a l and m e d ic al s ervices available at the medical ce nter h as fa c i lit ate d the cond uc t oft rials.

and_have pioneered_the treatment of children_and pregnant_women_with HIV_infection_through both Phase_I and Phase_II/III trials. Over 90%_of the women_and_children recruited into treatment protocols have been members of minority groups. The extensive infrastructure_of_social and_medical_services_available at the medical center_has facilitated the conduct of_trials.


the information that originates in taste receptors, and will thereby provide greater understanding of the role of the gustatory system in feeding and feeding-related disorders. Successful treatment of metastasis continues to be the main challenge in cancer. Local chest wall recurrences of breast cancer often occur in the context of metastatic disease, presenting the challenge

the information that originates in taste receptors, and will thereby leave great understanding of the role of the gustatory system in eating and feeding - related disorders. Successful discussion of metastasis continue to be the main challenge in cancer. Local chest wall recurrences of breast cancer much occur in the context of metastatic disease, presenting the challenge

thf information that origikates in taste rgcwptors, and wjll therdby provide greater understaidint of uke role of the gustagory systvm in feeeing qnd feedinj-delated disorscrs. Sbcressful treatmekt of metasdasis continuev go be the main challenge in cancer. Losal chext wall recurrenses ps brsast cancer often occur in the confext of metastatic dosease, presenting the chalpengf

the information that originates in taste receptors, thereby greater understanding the role of and disorders. Successful treatment metastasis continues to the main challenge in cancer. Local wall recurrences of breast cancer often occur in the context of metastatic disease, the challenge

the information that originaTes in taste RecepTorS, anD wIll tHereBy provide greatER undErstanding of the role of tHe gusTaTOry sYStEm in fEeding aND fEEDinG-rElAteD dISoRders. sucCessful Treatment oF meTaStasis continUEs To be the maiN chAllenge in canCer. local cHeSt wALl recUrrEnces Of breaST canceR often occUr IN the coNText of mETAsTatiC disease, presentinG ThE Challenge

the information that orig inates intaste  re cep to rs,andwill thereby p r ovid e greater understandin g ofth e  rol e  o f the  gustat o ry s yst em  i n f ee d in g and  fe eding-r elated dis ord er s. Successfu l  t reatment o f m etastasis co nti nues t obet he ma inchall enge i n  cance r. Localch e st wal l  recurr e n ce s of  breast cancer of t en occur in the c ontext  o f  m e t ast ati c disease,  p resen t ing the ch a l l eng e

the_information that_originates in taste receptors,_and will_thereby_provide greater_understanding_of the role_of the gustatory_system in feeding and_feeding-related disorders. Successful_treatment_of metastasis continues to be the main challenge in cancer. Local chest wall recurrences_of_breast cancer_often_occur_in the context of metastatic_disease, presenting the challenge


tension on axons spanning two populations of neurons in culture. As our central hypothesis, we propose that engineered living nervous tissue constructs will promote recovery after major peripheral nerve injury by providing a living labeled pathway to guide host axons from the proximal nerve stump across large nerve lesions to reinnervate the target tissue. In addition to providing

tension on axons spanning two populations of nerve cell in acculturation. As our central hypothesis, we nominate that mastermind living nervous tissue concept will promote recovery after major peripheral nerve wound by provide a living label pathway to guide master of ceremonies axon from the proximal nerve stump across big nerve lesions to reinnervate the prey tissue. In addition to providing

tejsion on axons spanning uwo populations oy neurois in chlture. Ar our central hypothesis, we 'ropise tyat engineered living vervous tpssue conwtrurts will promote recovern aftsv majmc peripheral netve injury bf providing a nixiug labeled pathway to guide host axogs from tje proximal netve suum[ acdoss large nerve lesions to reinnedvate tie target tissur. In addition to providing

tension on axons spanning two populations of culture. our central we propose that will recovery after major nerve injury by a living labeled pathway to guide axons from the proximal nerve stump across large nerve lesions to reinnervate the tissue. In addition to providing

tension on axons spanning two PopulationS of neUroNs iN cUltuRe. As Our central hypoTHesiS, we propose that engineerEd livInG NervOUs TissuE constrUCtS WIll PrOmOte ReCOvEry afTer Major peRipheral neRve InJury by providINg A living labEleD pathway to guIde Host axOnS frOM the pRoxImal nErve stUMp acroSs large neRvE LesionS To reinnERVaTe thE target tissue. In adDItIOn to providing

tension on axons spanning  two popul ation s o f n eu rons  inculture. As ou r  cen tral hypothesis, we pr opose  t h at e n gi neere d livin g  n e r vou sti ssu ec on struc tswill pr omote reco ver yafter majorp er ipheral ne rve  injury by p rov idingaliv i ng la bel ed pa thwayt o guid e host ax on s  fromt he prox i m al  ner ve stump across l a rg e  nerve lesions  to re in n er v a tethe  target ti ss ue. I n  additi o nt o pro v iding

tension_on axons_spanning two populations of_neurons in_culture._As our_central_hypothesis, we propose_that engineered living_nervous tissue constructs will_promote recovery after_major_peripheral nerve injury by providing a living labeled pathway to guide host axons from_the_proximal nerve_stump_across_large nerve lesions to reinnervate_the target tissue. In addition_to providing


higher bactericidal Ab against Nm than wild- type FHbp. We will also delete Rmp and H.8, which may elicit blocking Ab against Ng and Nm, respectively. Elicited Abs will be tested for complement-dependent bactericidal activity against homologous and heterologous Ng strains and tested for efficacy versus

higher bactericidal Ab against Nm than wild- type FHbp. We will also delete Rmp and H.8, which may arouse block Ab against Ng and Nm, respectively. Elicited Abs will be tested for complement - dependent bactericidal activity against homologous and heterologous Ng stress and tested for efficacy versus

hihher bactericidal Ab agalnst Nm than wilb- type HHbp. We will alro delete Rmp and H.8, which mab elucit vlocking Ab against Ng and Nm, rvspectiveoy. Eoucited Abs will be testes for romplement-depencent bactesicidal actividy ayainst homologous and heterologous Nd straims and tested fot effpcwcy bvrwus

higher bactericidal Ab against Nm than wild- We also delete and H.8, which Ng Nm, respectively. Elicited will be tested complement-dependent bactericidal activity against homologous and Ng strains and tested for efficacy versus

higher bactericidal Ab againSt Nm than wiLd- typE FHBp. WE wIll aLso dElete Rmp and H.8, whICh maY elicit blocking Ab againSt Ng aNd nM, resPEcTivelY. ElicitED ABS WilL bE tEstEd FOr ComplEmeNt-depenDent bacterIciDaL activity agaINsT homologouS anD heterologouS Ng StrainS aNd tESted fOr eFficaCy versUS

higher bactericidal Ab ag ainst Nm t han w ild - t yp e FH bp.We will also d e lete  Rmp and H.8, which ma y eli ci t  blo c ki ng Ab  agains t  N g and  N m,  re sp e ct ively . E licited  Abs willbete sted for com p le ment-depen den t bactericid alactivi ty  ag a insthom ologo us and hetero logous Ng  s t rainsa nd test e d  f or e fficacy versus

higher_bactericidal Ab_against Nm than wild-_type FHbp._We_will also_delete_Rmp and H.8,_which may elicit_blocking Ab against Ng_and Nm, respectively._Elicited_Abs will be tested for complement-dependent bactericidal activity against homologous and heterologous Ng strains_and_tested for_efficacy_versus


and tolerability. This R13 application proposes to support a 2-day annual meeting to enhance the collaborative network, and maximize the long-term national impact of the National Consortium for Multicultural Education for Health Professionals (Consortium). Funded in 2004 by NHLBI as a 5-year competitive training award program

and tolerability. This R13 application proposes to support a 2 - day annual merging to enhance the collaborative net, and maximize the long - term home impact of the National Consortium for Multicultural Education for Health Professionals (Consortium). fund in 2004 by NHLBI as a 5 - year competitive education award program

anf tolerability. This R13 apklication proposes to su'port a 2-day annjal meeting to enhance the clloaborqtive network, and maxioize the pong-term natmonal impact of vge National Ckksortnun for Multiculjural Educathon for Health Pfoyessionals (Consortium). Funded in 2004 by GHLBI ax w 5-year competijive urayninf award program

and tolerability. This R13 application proposes to 2-day meeting to the collaborative network, impact the National Consortium Multicultural Education for Professionals (Consortium). Funded in 2004 by as a 5-year competitive training award program

and tolerability. This R13 appliCation propOses tO suPpoRt A 2-day AnnuAl meeting to enhANce tHe collaborative network, And maXiMIze tHE lOng-teRm natioNAl IMPacT oF tHe NAtIOnAl ConSorTium for multicultuRal edUcation for HeALtH ProfessioNalS (Consortium). FUndEd in 2004 by nHlBI AS a 5-yeaR coMpetiTive trAIning aWard progrAm

and tolerability. This R1 3 applicat ion p rop ose sto s uppo rt a 2-day ann u al m eeting to enhance thecolla bo r ativ e  n etwor k, andm ax i m ize  t he  lo ng - te rm na tio nal imp act of the  Na ti onal Consort i um  for Multi cul tural Educat ion  for H ea lth Profe ssi onals  (Cons o rtium) . Fundedin 2004 b y  NHLBIa s  a  5-y ear competitive t r ai n ing award prog ram

and_tolerability. This_R13 application proposes to_support a_2-day_annual meeting_to_enhance the collaborative_network, and maximize_the long-term national impact_of the National_Consortium_for Multicultural Education for Health Professionals (Consortium). Funded in 2004 by NHLBI as a_5-year_competitive training_award_program


the study will also compare the use of a number of cell types with the goal of identifying the most sensitive and cost effective model system. This study will provide valuable baseline data on the potential for adverse health effects of PM in an airshed that has received almost no scientific attention. This subproject is one of many research

the study will also compare the use of a number of cellular telephone type with the goal of identifying the about sensitive and cost effective mannequin system. This study will supply valuable baseline data on the electric potential for adverse health effect of PM in an airshed that has receive almost no scientific attention. This subproject is one of many inquiry

thf study will also compart the use of a number of cell fypes wigh the goal of identifying tie mist stusitive and cost effdctive mofel systwm. Tiis study will pckvide valuabls baszlmne data on the potential for adverse haautk effects of PM in an airshed that hws receovfd almost no ssienuifyc afnektion. This subproject is one of jany revearch

the study will also compare the use number cell types the goal of cost model system. This will provide valuable data on the potential for adverse effects of PM in an airshed that has received almost no scientific attention. subproject is one of many research

the study will also compare thE use of a numBer of CelL tyPeS witH the Goal of identifyINg thE most sensitive and cost eFfectIvE ModeL SyStem. THis studY WiLL ProViDe ValUaBLe BaselIne Data on tHe potentiaL foR aDverse health EFfEcts of PM in An aIrshed that haS reCeived AlMosT No sciEntIfic aTtentiON. This sUbproject Is ONe of maNY researCH

the study will also compa re the use  of a  nu mbe rof c elltypes with the goal  of identifying the mo st se ns i tive an d cos t effec t iv e mod el  s yst em .  T his s tud y willprovide va lua bl e baseline d a ta  on the po ten tial for adv ers e heal th  ef f ectsofPM in  an ai r shed t hat has r ec e ived a l most no s ci enti fic attention. Th i ss ubproject is o ne ofma n yr e sea rch

the_study will_also compare the use_of a_number_of cell_types_with the goal_of identifying the_most sensitive and cost_effective model system._This_study will provide valuable baseline data on the potential for adverse health effects of_PM_in an_airshed_that_has received almost no scientific_attention. This subproject is one_of many_research


ured), several of whom have just joined the faculty this academic year. These investigators are from five basic science an| two clinical departments in the College of Medicine, as well as from two undergraduate departments with strong graduate training programs. This application contains both regular (18) and pilot (4) projects. The mantra for

ured), several of whom have just joined the faculty this academic class. These detective are from five basic science an| two clinical departments in the College of Medicine, equally well as from two undergraduate departments with solid graduate education programs. This application contains both even (18) and pilot (4) projects. The mantra for

uref), several of whom have jmst joined the fcxulty vhis aczdemic ydar. These investigators are hrom five basic science an| two zlinical fepartmebts mn the College oh Medicikz, as scll av from two undetgraduate de[artments with sgrlng graduate training programs. This applicstlon contains bjth gedulad (18) and pilot (4) projects. The mantra ror

ured), several of whom have just joined this year. These are from five departments the College of as well as two undergraduate departments with strong graduate programs. This application contains both regular (18) and pilot (4) projects. The mantra

ured), several of whom have just Joined the fAcultY thIs aCaDemiC yeaR. These investigATors Are from five basic sciencE an| twO cLInicAL dEpartMents in THe cOLleGe Of medIcINe, As welL as From two UndergraduAte DePartments witH StRong graduaTe tRaining progrAms. this apPlIcaTIon coNtaIns boTh reguLAr (18) and pIlot (4) projeCtS. the manTRa for

ured), several of whom hav e just joi ned t hefac ul ty t hisacademic year. Thes e investigators are fr om fi ve basi c  s cienc e an| t w oc l ini ca ldep ar t me nts i n t he Coll ege of Med ici ne , as well as fr om two und erg raduate depa rtm ents w it h s t ronggra duate  train i ng pro grams. Th is applic a tion co n t ai ns b oth regular (18)a nd pilot (4) proj ects.Th e  m a n tra  fo r

ured), several_of whom_have just joined the_faculty this_academic_year. These_investigators_are from five_basic science an|_two clinical departments in_the College of_Medicine,_as well as from two undergraduate departments with strong graduate training programs. This application_contains_both regular_(18)_and_pilot (4) projects. The mantra_for


and evolution of complex metazoan GRNs to gain insights into global mechanisms of gene regulation. It is becoming increasingly clear that textbook explanations of gene regulation in which a TF binds DNA in the genome and upon doing so regulates the most proximal gene are too simplistic because many physical TF binding events lack an apparent regulatory consequence.

and evolution of complex metazoan GRNs to gain insights into global mechanism of gene rule. It is becoming increasingly clear that textbook explanation of gene rule in which a TF binds DNA in the genome and upon doing thus regulates the most proximal gene are excessively simplistic because many physical TF binding consequence lack an apparent regulatory consequence.

anf evolution of complex mttazoan GRNs to gcun insmghts ihto globxl mechanisms of gene regulavion. It iw becoming increasinglh clear tjat textvook wxplanatioia of gekz reghpatimi in which a TF binds DNA in the genome avd upon doing so regulates the most pwoximal gfne are too siiplixeic gvccuse many physical TF binding ebents leck an apparent regulatory consequence.

and evolution of complex metazoan GRNs to into mechanisms of regulation. It is explanations gene regulation in a TF binds in the genome and upon doing regulates the most proximal gene are too simplistic because many physical TF binding lack an apparent regulatory consequence.

and evolution of complex metaZoan GRNs to Gain iNsiGhtS iNto gLobaL mechanisms of gENe reGulation. It is becoming inCreasInGLy clEAr That tExtbook EXpLANatIoNs Of gEnE ReGulatIon In which A TF binds DNa in ThE genome and upON dOing so reguLatEs the most proXimAl gene ArE toO SimplIstIc becAuse maNY physiCal TF bindInG Events LAck an apPAReNt reGulatory consequenCE.

and evolution of complexmetazoan G RNs t o g ain  i nsig htsinto global me c hani sms of gene regulation . Itis beco m in g inc reasing l yc l ear  t ha t t ex t bo ok ex pla nations  of gene r egu la tion in whic h  a  TF bindsDNA  in the geno meand up on  do i ng so  re gulat es the most p roximal g en e  are t o o simpl i s ti c be cause many physic a lT F binding even ts lac ka na p par ent  regulator yconse q uence.

and_evolution of_complex metazoan GRNs to_gain insights_into_global mechanisms_of_gene regulation. It_is becoming increasingly_clear that textbook explanations_of gene regulation_in_which a TF binds DNA in the genome and upon doing so regulates the_most_proximal gene_are_too_simplistic because many physical TF_binding events lack an apparent_regulatory consequence.