Thisproposalisafour-yearplanforaMentoredResearchScientistDevelopmentAward(K01),thegoalof whichistofacilitatethecareertransitionofXuanmao(Mao)Chenfromajuniorinvestigatorintofullresearch independence.ThisK01awardconsistsofaprogramdesignedtosupporthiscareerdevelopmentduringthis criticalperiodbyprovidingtraininginneurobiologyofaging,proteomicsandIlluminasequencingwhile enhancinghisexpertiseinthefieldofprimarycilia.TheprimarymentorwillbeRickCote,whoisawell- establishedscientiststudyingphosphodiesteraseinspecializedciliaofphotoreceptors.Chenwillalsobeco- mentoredbyDanielStorm,whoisawell-knownexpertinthefieldofadenylylcyclaseandcognition;?George Martin,whoisaprominentscientistinAlzheimer?sdisease;?andDavidClapham,whoisanoutstandingexpert ofprimarycilia.Thetrainingplanincludesstructuredmentorshipwithanadvisorycommittee,agrantwriting program,teachingworkshops,participationinresearchseminarsandtrainingcourses,andone-on-one mentorshipforteachingandresearch.TheresearchplanwillstudytheroleofcAMPsignalinginprimarycilia inhippocampaladultneurogenesisandbrainaging.Primaryciliaplayacriticalroleindevelopmentandtissue regeneration,butlittleisknownabouttheircontributionstobrainaging.Geneticevidencefromhumanpatients supportstheassociationbetweendefectsinprimaryciliaandcognitiveimpairmentandneurodegeneration. Chenwillfocushisstudyontype3adenylylcyclase(AC3),amajoradenylylcyclasecriticalforcAMPsignaling inneuronalcilia.Previously,ChenfoundthatAC3conventionalknockoutmiceexhibitage-relatedpleiotropic phenotypesincludingneuronalatrophy,synapticdysfunction,olfactorydeficit,memorydeficitsandalterationof sleeparchitecture.Chen,incollaborationwithRichardPalmiter,hasrecentlygeneratedanAC3floxedmouse strainthatwillbeusedtoablateAC3inatissue-andtime-dependentmanner.ChenhypothesizesthatcAMP signalingintheprimaryciliaofcentralneuronsissimilartothatinolfactorysensorycilia,andthatperturbations incAMPsignalinginneuronalprimaryciliainfluenceadultneurogenesisandbrainaging.Hewillfirstdevelop methodstomanipulatecAMPgenerationinprimaryciliatofacilitatethestudyofcAMPsignalinginprimary cilia,andthenidentifymolecularcomponentsthatmediatethecAMPsignaltransductionpathwayinneuronal primarycilia.HewillfurtherdeterminetheroleofAC3inneuronalprimaryciliainhippocampaladult neurogenesisandexamineiflossofAC3inadult-bornhippocampalneuronsleadstocognitivedeficits. Alternatively,hewillexaminethepotentialroleofAC3instresshormoneregulationandexamineifthereare age-associatedstructuralchangeswithneuronalprimarycilia.Together,completionofthisworkwillprovide foundationforChentodevelopastrongresearchprogramtorevealthefunctionofciliarycAMPsignalingand studythecontributionsofimpairedcAMPsignalinginneuronalprimaryciliatobrainaging.

Public Health Relevance

Primaryciliahavelongbeenconsideredremnantorganelles,buttheyhaverecentlygainedrecognitionasa nexusfordetectingavarietyofsignalsincludinghormonesandmorphogens.Chen?sgoalsaretofindnew methodstomanipulatecAMPinneuronalprimarycilia,identifysignalproteinsthatmedicatecAMPsignal transductionpathwayinneuronalprimarycilia,andinvestigatetherolesofAC3inhippocampaladult neurogenesisandbrainaging.ThisawardwillenableChentoelucidatethemolecularmechanismsofneuronal ciliarysignalingandrelatethemtobrainaging,aswellastrainhimtobemorecompetitiveforNIHR01-type grants.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01AG054729-01
Application #
9224464
Study Section
Neuroscience of Aging Review Committee (NIA)
Program Officer
Wise, Bradley C
Project Start
2017-09-15
Project End
2018-05-31
Budget Start
2017-09-15
Budget End
2018-05-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of New Hampshire
Department
Biochemistry
Type
Earth Sciences/Resources
DUNS #
111089470
City
Durham
State
NH
Country
United States
Zip Code
03824