Amyloid-like phase transition of Junctophilin-2 protein in heart aging
Junctophilin-2 蛋白在心脏衰老过程中的类淀粉样相变
基本信息
- 批准号:10593215
- 负责人:
- 金额:$ 7.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-30 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AgingAlanineAmyloidAmyloid ProteinsAmyloid depositionArchivesBiological AssayCardiacCardiac MyocytesCardiomyopathiesCause of DeathCell AgingCessation of lifeCharacteristicsConsequentialismCouplingDataDegenerative DisorderDependovirusDepositionDiagnosticDiseaseElderlyFluorescence Recovery After PhotobleachingFunctional disorderFundingGenetic TranscriptionGrowthHeartHeart failureHot SpotHumanIn VitroInterruptionKnowledgeLiquid substanceLong-Term EffectsMediatingMethodsMissense MutationModelingModificationMolecularMusMutationMyocardial dysfunctionMyocardiumNatureOrganPathologicPathologyPatientsPhasePhase TransitionPhenotypePhysiologicalPost-Translational Protein ProcessingProtein OverexpressionProteinsPublicationsReportingResearchRiskRoleSolubilitySourceStainsTherapeuticTimeTransmission Electron MicroscopyUnited Statesage relatedagedalpha helixbasebeta pleated sheetcardiac amyloidosiscell injurycytotoxicextracellulargene therapyheart functionhuman old age (65+)interdisciplinary approachjunctophilinmisfolded proteinmutantnovelolder patientoverexpressionpreventprotein aggregationtherapeutic targetthree dimensional structuretool
项目摘要
Abstract
Over 90% of heart failure deaths occur in patients over the age of 65. In many cases, cell aging is associated
with aberrant protein phase transition to cytotoxic amyloid-like aggregates, which can cause organ dysfunction
and degenerative diseases. It has been acknowledged that cardiac deposition of amyloids can cause damage
to the heart and result in an aggressive form of heart failure. Therefore, there is a great need to expand our
knowledge of potential cardiac amyloidogenic proteins. Junctophilin-2 (JPH2), a regulator of cardiac excitation-
contraction coupling and transcription, is a hot target for cardiomyopathy associated mutations, including a
mutation associated with diagnostic phenotypes of cardiac amyloidosis in aged patient. Our publication for the
first time discovered that JPH2 has an intrinsic capability to form amyloid-like aggregates. We have identified
mutations and possible posttranslational modifications that induce the aggregation of JPH2. Importantly, we
detected age-dependent phase transition of JPH2 into SDS insoluble state in mouse hearts. Based on these
preliminary data, we hypothesize amyloid-like JPH2 aggregation in cardiomyocytes can be induced by aging or
mutations, and consequentially contribute to cardiac dysfunction. This proposal specifically aims at 1.
characterize the amyloid nature of JPH2 aggregates; 2. defining the overall consequences of JPH2 aggregation
for cardiac function; 3. determining the effect of several human cardiomyopathy associated JPH2 mutations on
amyloid-like phase transition of this protein. This proposal is significant because defining the age-dependent
aberrant phase transition of JPH2 would provide new mechanisms and potential therapeutic targets for the aging
related heart dysfunction. JPH2 is conventionally considered to be beneficial for heart, and overexpression of
this protein is considered to be a therapeutic strategy. This study would reveal a pathological role of this protein
as a source of intracellular amyloids, and evaluate a potential hidden risk of overexpressing JPH2 in aging hearts.
This proposal is novel, because it offers an opportunity to define a novel cardiac amyloidogenic protein involved
in aging related cardiac pathology. We anticipate that the molecular tools, methods, and data generated through
the proposed studies will enable us to compete for long-term funding to systematically explore the pathological
significance and mechanisms of JPH2 amyloid phase transition in aging hearts.
摘要
项目成果
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{{ truncateString('Ang Guo', 18)}}的其他基金
Amyloid-like phase transition of Junctophilin-2 protein in heart aging
Junctophilin-2 蛋白在心脏衰老过程中的类淀粉样相变
- 批准号:
10708140 - 财政年份:2022
- 资助金额:
$ 7.25万 - 项目类别:
New Paradigm of Targeting COX-Catalyzed Free Radical Peroxidation in Colon Cancer
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9022113 - 财政年份:2016
- 资助金额:
$ 7.25万 - 项目类别:
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