Abstract

(CHEN,JI) Primaryciliaarethe?cellularantennae?thatdetectvariousextracellularsignalsincludinghormones.Defectsin primaryciliacauseabroadspectrumofhumandiseasesincludingobesity.Thetype3adenylylcyclase(AC3) isthemajoradenylylcyclaseandakeyenzymemediatingthecAMPsignalpathwayinolfactorysensorycilia andinprimaryciliathroughoutthecentralnervoussystem(CNS).AC3inolfactorysensoryciliaisessentialfor theolfactorysignaltransductionandlossofAC3leadstoanosmia(lossofsmell).Moreover,multiplegenetic evidencehasdemonstratedthatdefectsinAC3areassociatedwithobesityanddepression.Nevertheless,the functionalmechanismsofAC3,andthesignalingtransductionpathwayinprimaryciliaintheCNSremaintobe elucidated.Becauseolfactorysensoryciliaandneuronalprimaryciliaarestructurallyrelatedandsharea commonintraflagellarproteintransportsystem,wehypothesizethatthecAMPsignalingintheprimaryciliaof CNSneuronsresemblesthatinolfactorysensoryciliaandalterationofthissignalinginneuronalprimarycilia impactsobesityanddepression.Totestthishypothesis,wewillfirstusefluorescentnanoparticlesinco- immnunostainingexperimentsandtakeamassspectrometrybasedproteomicapproachtoidentifysignal proteinsthattransducethecAMPsignalingintheprimaryciliaofCNSneurons.Wewillnextgenetically engineeralight-activatedadenylylcyclaseintoprimaryciliatoenableoptogeneticmanipulationofcAMPlevel inneuronalprimarycilia.WewillalsodeterminehowcAMPinneuronalprimaryciliamodulateneuronal functions.Inaddition,wewillfurtheridentifywhichneuronalensembleswithlossofAC3leadstoobesityand depressionusingtissue-specificAC3knockoutmice.Completionofthisprojectwillidentifymolecular componentsthatmediateciliarycAMPsignaltransduction,generateusefultoolsforciliumresearch,and providenovelinsightsintothe(patho-)physiologicalrolesofAC3inobesityanddepression.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM113131-04
Application #
9937770
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost

  Institution

Name
University of New Hampshire
Department
Type
DUNS #
111089470
City
Durham
State
NH
Country
United States
Zip Code
03824

  Publications

Mohammadi, Mohammadjavad; Mohammadiarani, Hossein; Shaw, Vincent S et al. (2018) Interplay of cysteine exposure and global protein dynamics in small-molecule recognition by a regulator of G-protein signaling protein. Proteins :
Tooley, Christian A; Gasperoni, Charles H; Marnoto, Sabrina et al. (2018) Evaluation of Metal Oxide Surface Catalysts for the Electrochemical Activation of Amino Acids. Sensors (Basel) 18:
Ghosh, Sujoy; Khan, Niazul I; Tsavalas, John G et al. (2018) Selective Detection of Lysozyme Biomarker Utilizing Large Area Chemical Vapor Deposition-Grown Graphene-Based Field-Effect Transistor. Front Bioeng Biotechnol 6:29
Arral, Mariah L; Halpern, Jeffrey M (2018) Electrochemical Detection of NG-Hydroxy-L-arginine. ECS Trans 85:1163-1169
Charntikov, Sergios; Pittenger, Steven T; Pudiak, Cindy M et al. (2018) The effect of N-acetylcysteine or bupropion on methamphetamine self-administration and methamphetamine-triggered reinstatement of female rats. Neuropharmacology 135:487-495
Morales, Marissa A; Halpern, Jeffrey Mark (2018) Guide to Selecting a Biorecognition Element for Biosensors. Bioconjug Chem 29:3231-3239
Thompson, Garrett; Marnoto, Sabrina; Halpern, Jeffrey M (2017) Proper Controls to Electrochemically Evaluate Carotenoids using ?-Cyclodextrin Modified Surfaces. ECS Trans 80:1177-1187