Abstract

Schizophrenia(SCZ)isachronic,severeanddisablingmentalillnessthataffects1%ofthepopulation,yethas no effective treatment. Antipsychotic medications can interrupt positive symptoms such as hallucinations in a subsetofindividuals,buthavelittleimpactonnegative(socialwithdrawn)orcognitivesymptoms.Tremendous progressinhumangeneticsinthepastfewyearshasrevealedpolygenicriskfactorsunderlyingschizophrenia. Ourbestchancetodevelopthenextgenerationtherapeuticsforschizophreniareliesonourabilitytodiscover and validate novel biological risk factors implicated by the emerging SCZ genetics. CACNA1I is a risk gene identifiedbyGWAS,andencodethe?1functionalcoreoftheCaV3.3voltage-gatedcalciumchannels.Emerging evidencesconnectthefunctionofCaV3.3withafewclinicalobservationsintheschizophreniapatientsincluding sleep spindle deficits. We hypothesize that impaired CaV3.3 plays a role in mediating SCZ risk, and it representsapotentialnoveltargetforschizophrenia.Here,weproposetoutilizeaprimaryHTSscreen and a cascade of secondary physiological and cellular assays to identify positive and negative modulatorsthatregulateCaV3.3functionwithhighspecificity.BycombiningHTS,appropriatesecondary screens,alongwithsubsequentmedicinalchemistryoptimization,thismultidisciplinaryeffortisexpectedtoyield apanelofincisivechemicalprobestodissecttheexpandingbiologicalfunctionofCaV3.3inneurobiologyand schizophreniadiseasemechanism. 1

Public Health Relevance

Thereisanurgentneedtodevelopnewtreatmentforschizophrenia.MotivatedbytheemergingSCZgenetics andbiologicalevidences,weproposethatCaV3.3representapotentialnoveltargetforSCZ.Thisprojectutilizes aprimaryHTSscreenandacascadeofsecondaryassaystodiscoverpositiveandnegativemodulatorsthat regulateCaV3.3functionwithhighspecificity.Thismultidisciplinaryeffortisexpectedtoyieldapanelofincisive chemical probes to dissect the expanding biological function of CaV3.3 in neurobiology and schizophrenia diseasemechanism. 1

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH115045-02
Application #
9594160
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Yao, Yong
Project Start
2017-11-09
Project End
2020-10-31
Budget Start
2018-11-01
Budget End
2019-10-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
Broad Institute, Inc.
Department
Type
DUNS #
623544785
City
Cambridge
State
MA
Country
United States
Zip Code
02142

  Publications

Pan, Jen Q; Baez-Nieto, David; Allen, Andrew et al. (2018) Developing High-Throughput Assays to Analyze and Screen Electrophysiological Phenotypes. Methods Mol Biol 1787:235-252
Manoach, Dara S; Pan, Jen Q; Purcell, Shaun M et al. (2016) Reduced Sleep Spindles in Schizophrenia: A Treatable Endophenotype That Links Risk Genes to Impaired Cognition? Biol Psychiatry 80:599-608