annexin a2 ( a2 ) belongs to the annexin family of ca - regulated phospholipid binding proteins , which are expressed in plants , animals , and protists throughout the phylogenetic tree . a2 is a 36-kilodalton protein produced by endothelial cells , monocytes , macrophages , trophoblast cells , and some tumor cells and exists both free in the cytoplasm and in association with intracellular and plasma membrane surfaces [ 2 , 3 ] . the human anxa2 gene consists of 13 exons distributed over 40  kb of genomic dna on chromosome 15 ( 15q21 ) . among mammalian species for which a2 has been sequenced , identity is approximately 98% at the amino acid level . when a2 is membrane associated , the tightly packed , alpha - helical 33-kda core domain forms a disk whose convex face is associated with membrane phospholipid and whose concave face is oriented away from the membrane . membrane binding is mediated by at least two potential ca - binding  annexin  repeats , features common to all annexin family proteins . while the core domains of the annexin proteins are relatively well conserved , the hydrophilic amino - terminal tail  or  interaction  domains are highly variable and essentially unique to each family member . protein s100a10 , also known as p11 , is a well - described binding partner of a2 [ 7 , 8 ] . as a member of the s100 family of proteins , p11 contains ca - binding helix - loop - helix motifs and confers increased phospholipid binding affinity on a2 . typical s100 proteins undergo a conformational change upon ca - binding that places helix iii ( hiii ) in a perpendicular orientation relative to helix iv(hiv ) , thus forming a cleft that can accept associated target proteins . this calcium activation rule , however , does not apply to p11 , which has permanently assumed a  calcium - on  state , due to replacement of the bidentate e by s , and the monodentate d with c . the published crystal structure of p11 in complex with the n - terminal 13 amino acids of a2 suggests that the basic unit of p11 structure is a noncovalently linked homodimer , each component of which can bind the a2 tail peptide to form a heterotetramer . upon binding , the a2 tail peptide assumes an -helical conformation that presents key hydrophobic residues ( v , i , l , and l ) within a cleft formed by loop l2 and helix hiv of one monomer and helix hi of the other . the c - terminal region of p11 , particularly its hydrophobic residues within the c - terminal extension ( yfvvhm ) , such as y and f , contributes critical contact points for binding to a2 . the primary fibrinolytic protease , plasmin , is formed upon cleavage of plasminogen at a single peptide bond at position r - v by either of two serine proteases , tissue plasminogen activator ( tpa ) , produced by vascular endothelial cells , or urokinase ( upa ) [ 1113 ] . tpa - dependent plasminogen activation is dramatically accelerated in the presence of fibrin , and to a lesser extent by cell surface fibrinolytic receptors . upar is expressed by monocyte / macrophages , tumor cells , and activated endothelial cells [ 14 , 15 ] , while the ( a2p11)2 complex is expressed on both resting and activated endothelial cells [ 16 , 17 ] . in addition , an interesting array of plasminogen - binding receptors , including -enolase , tata - box protein interacting protein ( tip49 ) , histone h2b , m2 integrin , amphoterin , and plg - rkt , have been identified on many cell types . on cell surfaces , the ( a2p11)2 complex serves as an assembly site for plasminogen and tpa [ 16 , 17 , 25 , 26 ] . although it is clear that heterotetramer - mediated colocalization of activator and substrate accelerates plasmin generation , there are , interestingly , two main theories as to the exact site of interaction of plasminogen and tpa with components of the heterotetramer complex . while one group suggests p11 as the key ligand interaction site and annexin a2 as the molecule that anchors it to the plasma membrane , another proposes annexin a2 , in complex with p11 , as the ligand binding site . a third group has suggested that , in the context of the cell surface and its proteolytic milieu , both annexin a2 and p11 may have exposed lysine residues that are accessible to the lysine binding  kringle  domains of both tpa and plasminogen . translocation of a2 to the outer leaflet of the plasma membrane of the endothelial cell is a key regulatory step governing vascular fibrinolysis [ 16 , 17 ] . although cell surface appearance of a2 has been linked to plasma membrane fusion of multivesicular bodies in nih 3t3 fibroblasts , and as a consequence of membrane disruption upon exocytosis of secretory granules in chromaffin cells , it is not clear whether similar mechanisms apply to the endothelial cell . endothelial cell translocation , which can occur within minutes , is initiated by several factors including heat stress , thrombin stimulation , and hypoxia [ 3032 ] and is known to require the presence of adequate p11 as well as src kinase phosphorylation at y. a2 was originally identified as a src kinase substrate , and translocation is driven by activation of pp60src . translocation of a2 to the cell surface is dependent upon the abundance of p11 . in the endothelial cell , p11 is stabilized by a2 , which , upon binding , masks a critical  degron ,  or polyubiquitination site on p11 . in the absence of sufficient a2 , p11 is polyubiquitinated and targeted to the proteasome for degradation . in anxa2 mice , which demonstrate low to nondetectable p11 expression , treatment with bortezomib , a proteasome inhibitor , restored p11 expression , verifying its regulation via a proteasome - linked pathway in vivo . in nonendothelial cells , p11 may be stabilized by one or more of its other partner proteins , which include a number of transmembrane channels and membrane receptors , such as the tetrodotoxin - resistant sodium channel nav1.8 , the two predomain k channel task-1 , the acid - sensing ion channel asic1a , the transient receptor potential channels trp5 and trp6 , and the 5ht-1b serotonin receptor . protein kinase c-(pkc- ) mediated phosphorylation of s or s residues on a2 appears to represent an additional regulatory pathway . serine phosphorylation within the tail domain of a2 dissociates the heterotetramer complex , preventing further translocation to the cell surface by allowing polyubiquitination of p11 and its degradation in the proteasome [ 40 , 41 ] . this event appears to be initiated by plasmin , which , once generated , signals activation of conventional pkc and thus limits its own generation . this mechanism appears to require cleavage of a2 by plasmin as well as activation of toll - like receptor 4 . in this paper , we summarize evidence from both animal models and human studies on the in vivo functions of the annexin a2/s100a10 system . the concept of the  annexinopathy  was first proposed in 1999 , and expanded in several subsequent reviews [ 4347 ] . here , we focus exclusively on the growing body of evidence that annexin a2 and its partner protein p11 contribute to human health and disease . the anxa2 mouse has been highly informative in investigating the role of the annexin a2 system in vascular homeostasis in vivo . although a2-deficient mice display normal development , fertility , and lifespan , fibrin accumulation is evident in both intravascular and extravascular locations within the lungs , spleen , small intestine , liver , and kidney ( figure 1 ) . microvascular endothelial cells isolated from anxa2 mice , moreover , lack the ability to support tpa - dependent plasmin generation in vitro , and arterial injury in vivo leads to an increased rate and severity of vascular occlusion in the anxa2 mouse . recently , fibrinolysis was also assessed in p11-null mice , which also displayed increased vascular fibrin , reduced clearance of thrombi , and impaired neovascularization of matrigel thrombi . interestingly , mice with diet - induced hyperhomocysteinemia share this phenotypic feature with the anxa2 mouse ( figure 1 ) . homocysteine ( hc ) is a thiol - containing amino acid that is generated during the conversion of methionine to cysteine . elevated levels of circulating hc have been associated with both thrombotic and atherosclerotic vascular disease , although therapies that lower plasma hc have not been shown to reduce the risk of recurrent cardiovascular disease . pretreatment , but not cotreatment , of endothelial cells with hc blocks their ability to bind tpa and inhibits endothelial cell - related , tpa - dependent plasminogen activation . incubation of purified a2 with hc , moreover , interferes with its ability to bind tpa . when wild type mice were subjected to diet - induced hyperhomocysteinemia , fibrin accumulated in multiple tissues ( figure 1(d ) ) , and extracted a2 failed to support tpa binding or tpa - dependent plasmin generation , revealing that hc - induced blockade of the cell surface a2 pathway can occur in vivo . the potential clinical utility of recombinant annexin a2 protein ( ra2 ) in ischemic stroke has emerged from thrombosis models in rats . animals were treated with low - dose tpa with or without ra2 at 2 or 4 hours following the initiation of focal embolic stroke . those receiving both agents had a significantly lower infarct size and greater cerebral blood flow compared to animals treated with low - dose tpa alone . in similar experiments , in which animals underwent middle cerebral artery embolization with autologous clot , pretreatment with ra2 not only improved blood flow but also reduced infarct size compared to saline - treated controls . these findings are significant in view of reported neurotoxicity and cerebral hemorrhage associated with the use of tpa in the treatment of thrombotic stroke in humans [ 5759 ] . thus , ra2 or related agents may constitute a useful adjunct to tpa alone for the restoration of cerebral blow flow . a2 or its analogs might also prove efficacious in the treatment of peripheral arterial occlusion . when carotid artery thrombosis was induced by adventitial application of fecl3 , administration of recombinant full length , but not truncated , a2 was associated with improved cerebral blood flow and reduced thrombus size in comparison with untreated control animals . this treatment had no effect on bleeding time , prothrombin time , or activated partial thromboplastin time , indicating that global clotting parameters remained intact . thus , a2 or its analogs may constitute a useful adjuvant to conventional thrombolytic treatment by reducing the effective dose of tpa , thereby limiting its potential toxicity .   the fibrinolytic system appears to modulate the development of plaque - like vascular lesions in mouse models of atherosclerosis in a complex fashion . mice deficient in both plasminogen and apolipoprotein e ( apoe ) , for example , display an enhanced tendency toward atherosclerosis compared to those lacking apoe alone , suggesting that plasminogen protects against lesion formation . on the other hand , when macrophages overexpressed upa in apoe mice , plaque development was accelerated through a plasminogen - dependent pathway . when apoe deficiency is combined with global deficiency of either upa or tpa , however , the predilection for early fatty streaks and advanced plaque development was similar to that seen in mice with isolated apoe deficiency . these data suggest that the fibrinolytic system acts at multiple levels in the regulation atherogenesis . in order to determine whether blocking plasmin(ogen ) binding to a2 on the surface of macrophages is an effective strategy to reduce the development of atherosclerosis , apoe mice were crossed with anxa2 mice to generate double nulls ( figure 2 ) . following weaning , apoeanxa2 mice were placed on a western chow diet ( 30% fat ) and sacrificed at 12 or 24  wks . aortas were removed and evaluated for lesion development by en face oil red o staining and morphometry of histologic sections taken through the aortic root at the base of the heart . there was no difference in en face lesion area or lesion size in apoeanxa2 mice as compared to apoeanxa2 mice . therefore , we conclude that the redundant nature of plasmin(ogen)-binding sites on macrophages renders targeting a single binding site ineffective in modulating lesion development in this model system . although embryonic vasculogenesis appears to be normal , anxa2 mice display diminished neovascularization in several in vivo assays , including matrigel implant , corneal pocket , and oxygen - induced retinopathy ( oir ) models . mice with diet - induced hyperhomocysteinemia also display impaired corneal neoangiogenesis , which can be corrected upon intravenous injection of recombinant annexin a2 . microvascular endothelial cells from anxa2 mice , as well as hc - treated human endothelial cells , moreover , migrate less efficiently in growth factor - enriched matrigel . together , these data suggest that absence of a2 , or its modification by hc , leads to impairment of angiogenesis - related endothelial cell function . interestingly , annexin a2 is upregulated in oir ( figure 3 ) . in this model , newborn mouse pups are transitioned to room air after 5 days in a 75% oxygen environment , whereupon relative hypoxia initiates a robust vascular proliferative response in the retina . the return to 21% oxygen also triggers a2 synthesis out of proportion to the increase in vascular endothelial cell abundance . a2 expression is also increased in the endothelial cell under true hypoxia through the direct action of hypoxia - inducible factor-1 ( hif-1 ) with the a2 promoter . electrophoretic mobility shift experiments , chromatin immunoprecipitation studies , and luciferase promoter reporter assays all indicate binding of hif-1 and hif-1 to a hypoxia - responsive element within the promoter region of the human a2 gene , leading to its activation . although oir - associated retinal neovascularization is impaired in the anxa2 mouse , it can be reestablished upon treatment of anxa2 mice with a subretinal injection of an a2-encoding adenovirus , which restores a2 expression . in addition , neovascularization of the hyperoxia - treated anxa2 retina can be repaired upon treatment with the defibrinating agent ancrod , which depletes fibrinogen , thereby preventing fibrin formation . together , these findings provide a link between fibrin accumulation and diminished neoangiogenesis and imply that new therapeutic avenues for proliferative retinal vascular disorders , such as retinopathy of prematurity or diabetic retinopathy , could involve blockade of a2 in addition to inhibition of angiogenic growth factors . in the central nervous system , glioblastomas , malignant tumors derived from glial cells , are usually highly aggressive and refractory to treatment due to the early development of widespread infiltrative loci . glioma - generated proteases , such as plasminogen activators and matrix metalloproteinases , contribute substantially to glioma cell invasion [ 67 , 68 ] . high concentrations of annexin a2 , similarly , are associated with the pseudopodia of invasive glioma cells , and knockdown of a2 reduces their migratory capacity in vitro . in both mouse and rat in vivo models , stable knockdown of a2 expression in glioblastoma cells retarded overall tumor progression upon implantation of the cells into rodent brains ; cellular invasion , proliferation , apoptosis , and angiogenesis interestingly , when a2 expression was stably reduced by transfection of rnai directed against a2 in rat gl261 glioma cells , tumor growth and invasiveness were reduced , even though p11 expression persisted ; this result indicated that the contribution of a2 to tumor invasiveness was p11 independent ( figure 4 ) . these data suggest that a2-directed treatment could offer a new therapeutic modality for human glioblastoma . in a xenograft model in which highly invasive and metastatic breast cancer cells were implanted into nude mice , both tumor growth and vascular density the tumor cells employed in this experiment expressed abundant a2 , strongly supported tpa binding and tpa - dependent plasmin generation and exhibited plasmin- and a2-dependent cellular matrix invasion [ 72 , 73 ] . these studies suggest that a2 may contribute to aggressive breast cancer cellular invasion and tumor angiogenesis through production of localized protease activity .   in a third in vivo model , growth of lewis lung and t241 sarcoma tumors implanted into p11-deficient mice impaired tumor growth was correlated with diminished macrophage density within the tumors , and clodronate - mediated depletion of macrophages in wild type mice led to a similar reduction in tumor size . this study recapitulates the finding that thioglycollate - induced macrophage invasion into the peritoneum , and macrophage invasion of subcutaneous matrigel plugs , were also impaired in the p11 knockout mouse . a related study reveals that soluble ( a2p11)2 tetramer activates human and murine monocyte - derived macrophages , that this activation requires toll - like receptor 4 ( tlr-4 ) , and that the tetramer modulates cytokine production in the macrophage . thus , tumor infiltration by macrophages may in part be due to ( a2p11)2 tetramer signaling . nevertheless , aseptic osteolysis , due to generation of wear debris particles ( wdp ) , is an emerging problem that leads to failure of 1030% of all joint replacements . alkane polymers , 812 carbon atoms in length and derived from the breakdown of wdp , bind directly to toll - like receptors 1 and 2 and activate the downstream signaling pathway . in addition , endocytosed wdp can induce endosomal membrane damage and disruption in phagocytic cells , and this process is associated with dramatic recruitment of cytoplasmic annexin a2 to the endosomal membrane ( figure 5 ) . in the absence of a2 , endosomal disruption leads to leakage of lysosomal cathepsins and h ions into the cytosol with subsequent activation of the nlrp inflammasome and an accelerated inflammatory response . a large body of work has focused on the role of p11 in neuropsychiatric function . p11 binds to both the serotonin 1b and serotonin 4 receptors , suggesting a role for p11 in regulation of mood . p11-deleted mice show depression - like behavior , characterized by increased immobility in the tail suspension test , increased thigmotaxis , and decreased responsiveness to a sucrose reward . in wild type mice , adenovirus - mediated deletion of p11 specifically within the nucleus accumbens ( na ) resulted in depressive behavior , indistinguishable from that seen in mice with global p11 deficiency ; exogenous administration of p11 within the na of p11-deleted mice restored normal behavior . these data correlate with findings in human depression , in which p11 protein levels were reduced in the na . furthermore , reduced p11 mrna levels in peripheral blood mononuclear cells may serve as a potential biomarker for patients at high risk of suicide . these studies raise the possibility that some forms of human depression may be reversible by augmentation of p11 expression . indeed , commonly used anti - inflammatory drugs that attenuate the antidepressive effects of serotonin reuptake inhibitors may do so by inhibiting the effects of interferon , a known inducer of p11 [ 82 , 83 ] . the tetrodotoxin - resistant sodium channel ( nav1.8/sns ) , whose expression is restricted to sensory neurons , is the major pain perception receptor and is expressed in 85% of neurons emerging from the dorsal route ganglia . p11 binds to the amino terminus of the nav1.8 protein and promotes its translocation to the plasma membrane to produce functional channels . deletion of p11 specifically in primary nociceptor sensory neurons was achieved using nav1.8 promoter - directed cre recombinase and led to a loss of tetrodotoxin - resistant sodium current density , and severe compromise of noxious coding in sensory neurons from the dorsal root horn . thus , directed p11 targeting may prove useful in the treatment of refractory pain disorders . at diagnosis , acute promyelocytic leukemia ( apl ) is commonly associated with life - threatening hemorrhage . in apl , clonal expansion of immature promyelocytes harboring a balanced chromosomal translocation ( t(15 ; 17)(q2224 ; q1221 ) ) gives rise to the transcriptionally active promyelocytic leukemia - retinoic acid receptor  ( pml - rar ) fusion protein . apl frequently responds to differentiation therapy with all - trans retinoic acid ( atra ) , which triggers degradation of pml - rar . while disseminated intravascular coagulation promotes coagulopathy in apl , consumption of the plasmin inhibitor alpha2-antiplasmin and development of a hyperfibrinolytic state due to excessive plasmin generation high - level expression of annexin a2 occurs specifically in apl blast cells ( figure 6 ) . a2 was detected in blast cells recovered from 6 of 6 apl patients , all of whom had evidence of hyperfibrinolysis , as evidenced by elevated circulating fibrin degradation products and d - dimer and depletion of plasma fibrinogen . nb4 cells , which carry the t(15 ; 17 ) translocation and express the pml - rar fusion protein , displayed steady state a2 mrna levels that were approximately 10-fold higher than those found on leukemia cells that lacked the fusion protein . treatment of nb4 cells with the retinoic acid receptor ligand , all - trans retinoic acid ( atra ) , attenuated a2 expression in a time frame associated with clinical resolution of bleeding . intracranial bleeding , an unusually frequent problem in apl , may be due to the relatively high level expression of the a2 system on cerebral microvascular endothelial cells compared to those of other vascular beds . elevated expression of p11 in nb4 cells was also recently demonstrated and shown to respond to treatment with atra . in a second clinical study , a cohort of 26 patients were studied prospectively and found to have enhanced fibrinolysis at diagnosis , despite normal tpa levels and increased pai-1 . apl cells harvested from these subjects expressed 3-fold higher levels of a2 , and their rate of tpa - dependent plasmin generation was similarly elevated over that seen in the presence of m1 , m2 , m4 , or acute lymphoblastic leukemia cells . both elevated a2 expression in blast cells and hyperfibrinolytic hemorrhage corrected in 23 patients upon treatment with differentiation therapy , consisting of all - trans retinoic acid ( atra ) or atra plus arsenic trioxide . this study confirms the role of the a2 system in fibrinolytic bleeding in patients with apl . expression levels of annexin a2 have been examined in a variety of human malignancies . in some , such as renal cell [ 9092 ] , gastric , prostate , pancreatic , breast   carcinoma , and osteogenic sarcoma , increased expression levels appear to correlate with higher histologic grade and/or development of distant metastases . in human glioblastoma , a2 expression correlates with histologic grade and cns dissemination [ 49 , 9799 ] . in human breast cancer , a2 appears to be associated with the surface of invasive , malignant cells , but not normal ductal or acinar epithelial cells , and expression correlated with neoangiogenic activity . proteomic profiling of colorectal cancer , moreover , revealed differentially increased expression of a2 in tumors that had progressed to lymph node metastases versus localized tumors . primary multiple myeloma cells harvested from a cohort of patients displayed 10-fold higher cell surface a2 expression than that observed on normal plasma cells ; silencing of a2 in related cell lines suppressed expression of proangiogenic genes . a2 and a related a2-binding  receptor  has been reported to promote myeloma cell adhesion and growth in the bone marrow . on the other hand , a2 expression in oral squamous cell carcinoma   or sinonasal adenocarcinoma these studies suggest that expression levels of a2 may have prognostic value in malignancy , but would need to be validated for each specific tumor . high levels of both p11 and a2 were found in 100% of anaplastic thyroid carcinomas , and correlated with their aggressive behavior . in a comprehensive study of s100 gene expression in over 300 primary breast cancers , both p11 ( s100a10 ) and s100a11 were selectively upregulated in basal versus nonbasal breast cancer subtypes , but did not predict overall survival . among 62 cases of human esophageal squamous cell carcinoma , 11 of 12 s100 genes , including p11 , were downregulated , based on reverse transcription - polymerase chain reaction assays . p11 transcripts have also been reported to be increased in both renal cell and gastric carcinomas [ 92 , 108 , 109 ] . further studies may define p11 expression as a viable biomarker or prognostic indicator in selected tumors . it is characterized by thrombosis and recurrent fetal loss in association with circulating antiphospholipid antibodies . the latter are distinct , often coexisting antibodies directed against either 2-glycoprotein i or other intravascular proteins , which may be found in complex with anionic membrane phospholipids . a2 has been identified as a prominent target of autoantibodies arising specifically in patients with aps with severe thrombosis and/or pregnancy morbidity [ 112 , 113 ] . in vitro , patient - derived antiannexin a2 antibodies blocked endothelial surface tpa - dependent plasmin generation , and also  activated  cultured endothelial cells , inciting them to express elevated levels of the prothrombotic agent , tissue factor . other groups have noted that a2 can serve as a binding site for (2)-glycoprotein i   in aps and can initiate a2-dependent endothelial cell activation . together , these data implicate a2 in the pathogenesis of aps - associated thrombosis through several possible mechanisms . cerebral venous thrombosis is a rare disorder of unknown etiology that mainly affects children and young adults . among a cohort of 40 consecutive patients studied 2 to 6 months following the index thrombotic event , 12.5% were found to have high titer anti - a2 antibodies compared to 2.1% in healthy subjects . thus , anti - a2 may define a new subset of individuals with immune - mediated thrombosis , play a role in the pathogenesis of this disorder , and/or offer novel therapeutic targets . both a2 and p11 are expressed on the brush border of the placental syncytiotrophoblast . in 60 patients with preeclampsia , a2 mrna and protein levels in placenta high titer anti - a2 antibodies , moreover , were detected more frequently in sera from subjects in the pre - eclamptic group and associated with increased placental vascular thrombosis . impaired local fibrinolytic function due to blunted a2 expression may contribute to the pathogenesis of pre - eclampsia and maternal and perinatal infant morbidity . sickle hemoglobinopathy arises from a point mutation within the 6th codon of the human -globin chain . polymerization of abnormal hemoglobin under deoxygenating conditions induces erythrocyte shape change and non deformability , which leads to vascular occlusion , impaired vasodilatation , distal ischemia , and endothelial cell activation with adhesion of leukocytes . in children a recent analysis of 108 single nucleotide polymorphisms in 39 candidate genes revealed that variations in the annexin a2 ( anxa2 ) gene , among several others , were associated with increased risk of stroke . a second independent study linked anxa2 polymorphisms to increased risk for stroke in sickle cell disease , while additional anxa2 snps have been associated with avascular necrosis of bone ( osteonecrosis ) in sickle hemoglobinopathy . these data suggest that annexin a2 may represent a significant modifier gene that shapes the clinical expression and natural history of sickle cell disease .
since its discovery as a src kinase substrate more than three decades ago , appreciation for the physiologic functions of annexin a2 and its associated proteins has increased dramatically . with its binding partner s100a10 ( p11 ) , a2 forms a cell surface complex that regulates generation of the primary fibrinolytic protease , plasmin , and is dynamically regulated in settings of hemostasis and thrombosis . 
 in addition , the complex is transcriptionally upregulated in hypoxia and promotes pathologic neoangiogenesis in the tissues such as the retina . 
 dysregulation of both a2 and p11 has been reported in examples of rodent and human cancer . 
 intracellularly , a2 plays a critical role in endosomal repair in postarthroplastic osteolysis , and intracellular p11 regulates serotonin receptor activity in psychiatric mood disorders . in human studies , the a2 system contributes to the coagulopathy of acute promyelocytic leukemia , and is a target of high - titer autoantibodies in patients with antiphospholipid syndrome , cerebral thrombosis , and possibly preeclampsia . 
 polymorphisms in the human anxa2 gene have been associated with stroke and avascular osteonecrosis of bone , two severe complications of sickle cell disease . 
 together , these new findings suggest that manipulation of the annexin a2/s100a10 system may offer promising new avenues for treatment of a spectrum of human disorders .