Role of Activin Type II receptor signaling in age-related heart failure
激活素 II 型受体信号传导在年龄相关性心力衰竭中的作用
基本信息
- 批准号:10540381
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-02-01 至 2022-12-02
- 项目状态:已结题
- 来源:
- 关键词:ActivinsAcuteAgeAgingAnimal ModelAortic Valve StenosisBindingBiological AssayBiologyBiomechanicsBone Morphogenetic ProteinsCalciumCardiacCardiac MyocytesClinicalClinical DataClinical ResearchCollaborationsComplexConflict (Psychology)CouplingDataDevelopmentDiseaseElderlyFSTL3 geneFoundationsFutureGDF11 geneGDF8 geneGeneticGoalsGrowth FactorHealthHeart failureHospitalizationHumanIn VitroInvestigationKnowledgeLearningLigandsLinkMass Spectrum AnalysisMeasurementMethodsMissionModelingMorbidity - disease rateMusMyocardial dysfunctionMyopathyOutcomePathway interactionsPatientsPeptidesPhenotypePopulationPost-Translational Protein ProcessingPrevalenceProcessProtein FamilyProtein IsoformsProteinsProteomicsPublic HealthPublishingReceptor ActivationReceptor SignalingRegulationReportingResearchResearch PersonnelRisk FactorsRoleSERCA2aSamplingSkeletal MuscleStressTechnologyType II Activin ReceptorsUnited States National Institutes of HealthWorkactivin Aage relatedbiobankcell typeclinical developmentclinically relevantcohortfrailtygain of functionin vivoin vivo Modelinhibitorinnovationinsightinterestloss of functionmorphogensmortalitymouse modelmultiple reaction monitoringolder patientpharmacologicpressurepreventtargeted treatmenttherapeutic targetvalve replacement
项目摘要
Heart failure (HF) is a major cause of morbidity and mortality in older adults, and currently represents
the leading cause of hospitalization in the elderly. Advanced age is one of the strongest risk factors for HF,
although why this is the case and whether it is possible to intervene in this process, remain unclear. In this
context, the role of Activin type II receptor (ActRII) ligands – and their potential catabolic effects in aging and
disease – has been a subject of intense interest and controversy in HF. There is a fundamental gap in our
understanding of how aging contributes to HF. Our over-arching hypothesis is that ActRII activation increases
with age as well as biomechanical cardiac stress, and contributes to cardiac dysfunction in multiple forms of
age-related HF. Our long-term goal is to understand the mechanisms linking ActRII signaling to cardiac
dysfunction and learn whether these pathways can be targeted for therapeutic benefit. The objective of the
current application is to examine the functional contribution of ActRII signaling in multiple age-related models
of HF, and to elucidate the underlying mechanisms. Our preliminary data suggest that activity of the ActRII
pathway increases with age, frailty, and HF in human cohorts, and with age and HF in mice. The increased
activity appears driven predominantly by Activin-A rather than other ligands. In mice, elevating Activin-A
levels was sufficient to cause cardiac dysfunction, while inhibition of the pathway in three distinct HF models
prevented or reversed HF. The translational importance of these findings is underscored by the existence of
pathway inhibitors currently in trials for other indications. The proposed work will be pursued in three
integrated Specific Aims. In Aim 1, we will use specific and effective gain- and loss-of-function models to
directly assess the role of ActRII signaling in HF, and to examine the role of ActRII in cardiomyocytes in vivo.
In Aim 2, we will elucidate the mechanism(s) by which ActRII leads to cardiac dysfunction. In Aim 3, we will
investigate the dynamic regulation of this pathway in biobanked samples from elderly patients with heart
failure using targeted mass spectrometry assays in collaboration with Dr. Steven Carr, Director of Proteomics
at the Broad Institute. The functional importance of correlative clinical data will be examined using in vivo
models, which will be supported by in vitro investigation of primary cardiomyocytes to elucidate the underlying
mechanisms. Our approach combines innovative hypotheses, technologies, unique animal models, and
translational work in relevant clinical populations with the complementary expertise of an outstanding team of
collaborating investigators. The proposed research is significant, because it is expected to advance our
understanding of age-related HF and delineate pathways relevant to aging and disease with the potential to
mitigate these clinically important conditions.
心力衰竭(HF)是老年人发病和死亡的主要原因,目前代表
项目成果
期刊论文数量(0)
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ANTHONY ROSENZWEIG其他文献
ANTHONY ROSENZWEIG的其他文献
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{{ truncateString('ANTHONY ROSENZWEIG', 18)}}的其他基金
Understanding the Cardiac Benefits of Exercise at the Cellular and Molecular Level
从细胞和分子水平了解运动对心脏的益处
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10322189 - 财政年份:2021
- 资助金额:
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Understanding the Cardiac Benefits of Exercise at the Cellular and Molecular Level
从细胞和分子水平了解运动对心脏的益处
- 批准号:
10889616 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Role of Activin Type II receptor signaling in age-related heart failure
激活素 II 型受体信号传导在年龄相关性心力衰竭中的作用
- 批准号:
10319962 - 财政年份:2019
- 资助金额:
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Discovery and characterization of lncRNAs involved in cardiac exercise phenotypes
参与心脏运动表型的 lncRNA 的发现和表征
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9885953 - 财政年份:2019
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-- - 项目类别:
Role of Activin Type II receptor signaling in age-related heart failure
激活素 II 型受体信号传导在年龄相关性心力衰竭中的作用
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10831299 - 财政年份:2019
- 资助金额:
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Role of Activin Type II receptor signaling in age-related heart failure
激活素 II 型受体信号传导在年龄相关性心力衰竭中的作用
- 批准号:
10063936 - 财政年份:2019
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Role of miR-222 in pathological hypertrophy and heart failure
miR-222在病理性肥厚和心力衰竭中的作用
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- 批准号:
8606241 - 财政年份:2013
- 资助金额:
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