Failureofdamagedaxonstoregenerateandreestablishfunctionalcircuitryistheprimarycausethatresultsin permanent disabilities after central nervous system (CNS) injury, and is also a major factor contributing to the non-reversibleneurologicdysfunctionseeninneurodegenerativediseases.Ofapproximately1.9%oftheU.S. population with paralysis, some 1,275,000 are paralyzed as the result of a spinal cord injury (SCI). SCIs frequentlyresultinatleastsomeincurableimpairmentevenwiththebestpossibletreatmentandpatientswith complete injuries recover very little lost function. Under pathological situations such as multiple sclerosis, the second most common neurological disorder leading to disability in young adults, failure of damaged axons to regeneratecontributestoneurologicabnormalities.Despiteampleeffortsinthepastfewdecades,whichhave ledtothediscoveriesofextracellularfactorsthatimpede,andintrinsicpathwaysinmatureneuronsthatdiminish the regenerative capacity of axons, effective therapies have not emerged given the fact that simply removing those inhibitory cues confers limited regrowth and that our understanding of neurons? intrinsic regenerative properties still remains incomplete, indicating that additional regulatory machinery must be in place. This highlightstheurgentneedtoidentifynovelmoleculartargetsfortherapy. WiththegoaltofindnovelfactorsessentialforCNSaxonregeneration,wehaveutilizedaDrosophilasensory neuron injury model that resembles mammalian injury at the phenotypical and molecular level in a candidate- basedgeneticscreen,andidentifiedthePiezo-Atr(AtaxiatelangiectasiaandRad3related)pathwayasinhibitors foraxonregeneration.ThisproposalaimstodeterminethecellularandmolecularmechanismsunderlyingPiezo- Atr?sfunctioninfliesandtoelucidatetheroleofthemammalianAtrafterperipheralorspinalcordinjury.Atris an essential component of the DNA damage response and also responds to mechanical force. This pathway hasneverbeenimplicatedinaxonregeneration,andourstudywillthusprovideexcitinginsightsintothepotential links among axon injury, DNA damage response, mechanosensation and regeneration, and will open new avenues of research for regeneration and spinal cord injury. Taking advantage of the power of fly genetics toidentifynovelfactorsandthemammalianinjurymodel,thisstrategyoffersauniqueopportunitytogaininsights intotherepertoireofregenerationregulators,whichmaydrivenoveltreatmentstopromoterecoveryinpatients withneuralinjuryorneurodegenerativediseases.
Centralnervoussysteminjurysuchasspinalcordinjuryisrefractorytorepair,attributedtothereduced neuronalintrinsicregenerationcapacityandahostilemicroenvironment.Understandingthemechanismsthat inhibitorpromoteneuralregenerationisrelevanttopublichealthbecauseitwillultimatelyleadtotreatments forneuralinjuryandneurodegenerativediseases.TheAtr(AtaxiatelangiectasiaandRad3related)pathway waspreviouslyknowntoregulateDNAdamageresponse,butherewedescribearemarkablenewfunctionof thispathwayininhibitingneuralregenerationthatlinksneuralregenerationtomechanosensation,andpropose Atrasanoveltherapeutictargetforneuralinjury,withdrugsalreadyinclinicaltrialsasanticancertherapy.
