Bipolardisorder(BD)isacommonmentalillnessthataffects1?2%oftheworld'spopulation,including>100,000 veterans,causingseveremoodsymptoms,volumetricoflossofbraingraymatter,andelevatedratesofsuicide.Among itssymptoms,BDisassociatedwithdisrupteddaily24hrrhythms(circadianrhythms)insleepandactivity.However, duetosimilaritiesandoverlapwithotherpsychiatricsyndromes,itiscommonlymisdiagnosedandtreatmentdelaysare frequent.LithiumisanexcellenttreatmentforBD,but30?50%oflithiumtreatedpatientsfailtorespondfullyto treatmentand/orsufferside?effects.Thesefactorscauseneedlessdelaysfromunsuccessfultreatment,increasingcost, disability,andextendingthewindoworriskforsuicide.Becauseofthesechallenges,newtechniquestodiagnoseBD, andmorerapidlyidentifylithiumresponderswouldbeoftremendousclinicalutility.Whilethesuprachiasmaticnucleus ofthehypothalamusisthe?masterclock?forcircadianrhythms,thegenesthatcontrolcircadianrhythms(?clock genes?)arefunctionalinperipheraltissuesandcanbestudiedinculturedskincells(fibroblasts)frompatients.Lithium haseffectsoncircadianrhythmsinfibroblasts,alteringtheexpressionofclockgenes,increasingrhythmamplitude (intensity)andlengtheningperiod(thedurationbetweencycles).Usingbioluminescentreportergenes(Per2::luc),one canaccuratelystudythecircadianclockintissuesfromBDpatientsandcontrols.Usingthisapproach,wehaveidentified clockgeneabnormalitiesinBD,andcircadianrhythmdifferencesinperiodthatdistinguishlithiumresponsiveandnon? responsiveBDpatients.Inotherstudies,wehaveidentifiedneurotrophinsaspharmacogeneticindicatorsoftherapeutic responsetolithiuminBDpatients.Interestingly,neurotrophinsareexpressedrhythmicallyunderthecontrolofthe circadianclock.Inthisproposal,weaimtoextenduponthisworkandsynthesizetheseobservationsto1)Establisha cellularmodeloflithiumresponsiveBDbasedoncelldeathandprotectionbylithium2)Determinetheeffectof circadianrhythmamplitudeonregulatingthevulnerabilityofneuronstooxidative/excitotoxiccelldeathand3) Determinetherelationshipbetweencircadianperiodandlithiumresponsiveness,focusingonneuroprotectionby lithium.Themethodologicalapproachismolecularandcellbased,usinggenetic(siRNAknockdown)and pharmacologicalmeanstomanipulatecircadianamplitude,periodandoverallrhythmicityinhumanfibroblasts,stem? cellderivedinducedneurons,andimmortalizedmousehippocampalneurons.Followingthesemanipulations, differencesincircadianrhythmparameters(amplitude/period)andcelldeathwillbemeasuredintheabsenceand presenceoflithium.Itisexpectedthatcellsfromlithium?responsivepatientswillbemoreabletobenefitfromthe protectiveeffectsoflithiumincelldeathassays.Furthermore,short?periodandhighamplituderhythmsincellswilllead togreaterresilienceunderconditionsofexcitotoxic/oxidativestress.Analysiswillbeconductedusingcurvefitting methodstomeasurerhythmsandunivariatestatisticalanalysestoidentifymeandifferencesincellsurvivalbasedon phenotypicorcircadianparameters.Whencomplete,thesestudiesmayprovidemechanisticinsightsintothe vulnerabilityfactorsunderlyingBD,andmolecularmechanismsunderpinninglithium'smodeofactionintreatingBD.By understandingtheseaspectsofBD,itmaybepossibleinthefuturetodeveloppredictorsoftreatmentresponse, diagnostictools,ornewtreatmentinterventionsbasedontheseresults.

Public Health Relevance

Bipolar disorder (BD) is a common mental illness that affects 1-2% of the world's population and ~100,000 veterans, causes mood symptoms, social/occupational disability and elevated rates of suicide. BD is associated with loss of brain volume and disruptions in daily (circadian) rhythms in sleep and behavior. Lithium is an inexpensive, effective treatment for BD that protects neurons, and restores circadian rhythms. However, 30-50% of patients with BD fail respond to lithium treatment and intolerable side effects are common. Lithium non-responsive patients are delayed in receiving effective treatment and require more expensive drugs. In order to gain insights that will allow for the future development of tools to identify lithium responsive patients rapidly, this study investigates the molecular interactions among circadian rhythms, neuroprotection and lithium in cell-based models of lithium response.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX003431-02
Application #
9431044
Study Section
Neurobiology R (NURR)
Project Start
2017-04-01
Project End
2021-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
VA San Diego Healthcare System
Department
Type
DUNS #
073358855
City
San Diego
State
CA
Country
United States
Zip Code
92161