Cellularsenescenceisatumorsuppressivecellgrowtharresttriggeredbyinducerssuchas activationofoncogenesandchemotherapeutics.However,senescentcellsareviableandmaypromote tumorprogressionandtherapyrelapsethroughsecretionoffactorssuchascytokines,chemokinesand growthfactors,termedthesenescence-associatedsecretoryphenotype(SASP).Thus,itwouldbeideal toenhancesenescence-associatedgrowtharrestwhilelimitingSASPbecausethismayleadtoadurable therapeuticoutcome.Notably,itremainstobedeterminedwhethersilencingofproliferationgenesand upregulationofSASPgenesarecoupledatthemolecularlevel.Thus,theoverallgoalofthisproposalis toinvestigatethemechanismthatcoordinatesthesilencingofproliferationgenesandtheupregulationof SASPgenesduringsenescenceanditsimplicationsincancerandresponsetotherapy.HMGB2isa chromatinarchitectureproteinthatbindstoDNAwithoutsequencespecificity.Ourpreliminarydata suggestthatHMGB2orchestratesgeneexpressionreprogrammingduringsenescencebyactingasa molecularswitch.Specifically,lossofHMGB2fromgenomiclociofproliferationgenescontributestotheir silencing.Incontrast,HMGB2?sredistributiontoSASPgeneslocipromotestheirexpression.Consistent withitsroleinsenescence,HMGB2isoftenupregulatedinepithelialovariancancer(EOC)andits expressioncorrelateswithEOCprogression.Further,expressionofHMGB2positivelycorrelateswithits targetproliferationgenesinEOCs.Basedonthesefindings,ourcentralhypothesisisthatHMGB2 orchestratesgeneexpressionreprogrammingtoregulatetheswitchfromproliferationtosenescence. WealsohypothesizethatHMGB2contributestoEOCbysuppressingsenescenceandpromotes platinum-basedtherapyrelapsebydrivingSASP.Accordingly,twospecificaimsareproposed:
Aim1 : ToelucidatethemolecularmechanismbywhichHMGB2regulatessenescence;?andAim2:To determinetheroleofHMGB2inEOCandtherapyrelapse.Theproposedstudiesarehighlynovel becausethisisthefirststudytoexploreanovelmolecularmechanismthatorchestratesthesilencingof proliferation-promotinggenesandtheupregulationofSASPgenesduringsenescence.Thus,ourstudies areparadigmshiftingintheirpotentialtoelucidatethemolecularbasisofgeneexpression reprogrammingduringsenescence.Theresearchproposedisofhighimpactbecausetheywilllaythe criticalfoundationforultimatelydevelopingnovelstrategiesthatharnessthetumor-suppressivebenefitof senescence,whilelimitingthedetrimentalaspectsofSASPtoultimatelyachievedurabletherapy outcome.Therefore,thecurrentstudywillnotonlyprovidecriticalmechanisticinsightsintogene expressionreprogrammingduringsenescence,butwillalsohavefar-reachingimplicationsforthe developmentofsenescence-basedtherapeuticstrategies.
Theproposedresearchisrelevanttopublichealthbecauseitwillrevealacriticalmolecular switchthatcontrolscellularsenescence,animportanttumorsuppressionmechanism.Thesemolecular insightsmayprovidescientificrationaletoultimatelydevelopnovelstrategieswithadurabletherapeutic outcomeforcancersincludingovariancancer,themostlethalgynecologicalmalignancyintheUnited States.Therefore,theproposedresearchisrelevanttothepartoftheNIH?smissionthatpertainsto developingfundamentalknowledgethatwillreducetheburdenofhumanillness.
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