Cardiac Sarcomere Protein Quality Control in Health and Disease
健康和疾病中的心脏肌节蛋白质量控制
基本信息
- 批准号:10445976
- 负责人:
- 金额:$ 53.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-04-01 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:ActinsAddressAutophagosomeBAG3 geneBindingBiological AssayBiophysicsCardiacCardiac MyocytesCellsClientComplexDataDepressed moodDiseaseFoundationsFunctional disorderFutureGenerationsGrantHalf-LifeHealthHeartHeart failureHeat-Shock Proteins 70Heat-Shock ResponseHumanImpairmentIn VitroKnockout MiceKnowledgeLasersLysosomesMechanical StressMediatingMental DepressionMethodsModelingModificationMolecular ChaperonesMusMuscle CellsMyocardial InfarctionMyosin ATPaseNatureNeonatalPathway interactionsPatientsPhenotypeProcessProteinsPublishingQuality ControlRattusRegulationResolutionRoleSarcomeresSedimentation processSignal TransductionStimulusStressStructureSystemTherapeuticTransgenic MiceTropomyosinUbiquitinUbiquitinationVentricularWorkcell motilitycostgene therapyimprovedin vivoinduced pluripotent stem celllive cell imagingmisfolded proteinnew therapeutic targetprotein degradationprotein protein interactionproteotoxicityrecruitresponsespatiotemporalubiquitin ligase
项目摘要
Cardiomyocytes are essentially non-renewing, so proteotoxicity from dysregulated Protein
Quality Control (PQC) is intimately associated with heart failure. The proteins that comprise the
cardiac sarcomere are responsible for force generation in the myocyte, and this constant mechanical
stress uniquely predisposes them to misfolding. Despite PQC’s central role in heart failure, and the
particular vulnerability of the sarcomere to misfolding, the PQC mechanisms that maintain the
cardiac sarcomere are almost entirely unknown. This is a critical knowledge gap that we will
address in this proposal. Our past work described a z-disc localized complex, anchored by the co-
chaperone Bcl2-associated athanogene-3 (BAG3), that was essential for sarcomere PQC. Z-disc
BAG3 levels were depressed in human heart failure (HF) and correlated with decreased sarcomeric
force-generating capacity (Fmax). Similarly, cardio-myocyte specific inducible BAG3 KO mice had
increased ubiquitination of sarcomeric proteins that remained integrated in the lattice, reducing force
generation. Importantly, BAG3 gene therapy in a mouse HF model reversed this phenotype,
indicating the potential of targeting sarcomere PQC to improve contractile function. In this renewal we
will address the central hypothesis that sarcomere PQC occurs via sarcomere-localized pathways
and depression of these systems in HF due to BAG3 instability results in accumulation of
ubiquitinated proteins that induce dysfunction. In Aim 1 we will Explore the spatiotemporal
organization of the key steps in sarcomere PQC. We will use super-resolution live cell imaging in
neonatal rat ventricular myocytes (NRVMs) and human iPSC-CMs to visualize the spatiotemporal
interplay between BAG3, autophagosomes, lysosomes, the z-disc, and BAG3-clients at baseline and
in response to various stress and stimuli, such as heat shock, localized laser damage, hypertrophic
signaling, and depressed BAG3 levels. In Aim 2 we will identify the functional consequences of
sarcomeric protein ubiquitination. We will use in vivo and in vitro approaches to modulate sarcomere
protein ubiquitination and assess the impact on sarcomere function with biophysical assays (force-
Ca2+ relationship, tension cost, in vitro motility assay, super-relaxed state, co-sedimentation). In Aim
3 we will discover the regulation of BAG3 in the cardiomyocyte and how it is altered in heart failure.
We will use several transgenic mouse lines and a myocardial infarction induced heart failure model,
to discover the interplay between HSP70, BAG3, heart failure, and sarcomere PQC. We expect to
identify new methods to stabilize BAG3 in the failing heart as a possible therapeutic strategy. These 3
aims establish a foundational understanding of sarcomere PQC, functional consequences of its
misregulation, and how it can be modulated in vivo.
心肌细胞基本上是不更新的,所以蛋白质毒性来自蛋白质失调
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JONATHAN A KIRK其他文献
JONATHAN A KIRK的其他文献
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{{ truncateString('JONATHAN A KIRK', 18)}}的其他基金
GSK-3β Localizes to the Myofilament and Modifies its Function in Ischemic Cardiomyopathy
GSK-3β 定位于肌丝并改变其在缺血性心肌病中的功能
- 批准号:
9287330 - 财政年份:2017
- 资助金额:
$ 53.92万 - 项目类别:
Cardiac Sarcomere Protein Quality Control in Health and Disease
健康和疾病中的心脏肌节蛋白质量控制
- 批准号:
10621229 - 财政年份:2017
- 资助金额:
$ 53.92万 - 项目类别:
GSK-3β Localizes to the Myofilament and Modifies its Function in Ischemic Cardiomyopathy
GSK-3β 定位于肌丝并改变其在缺血性心肌病中的功能
- 批准号:
9903442 - 财政年份:2017
- 资助金额:
$ 53.92万 - 项目类别:
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