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

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

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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
  • 批准号:
    10322189
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
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:
    --
  • 项目类别:
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
  • 批准号:
    9885953
  • 财政年份:
    2019
  • 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:
    10831299
  • 财政年份:
    2019
  • 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:
    10063936
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
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
  • 批准号:
    9250361
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Does Exercise Induce Cardiomyogenesis?
运动会诱导心肌生成吗?
  • 批准号:
    8916527
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
Does Exercise Induce Cardiomyogenesis?
运动会诱导心肌生成吗?
  • 批准号:
    8699591
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
Micro-RNA regulation of the cardiac exercise response
心脏运动反应的微小RNA调节
  • 批准号:
    8606241
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:

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急性髓性白血病的年龄因素、突变和化学抑制剂
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急性和慢性 GPCR 药物心脏保护:受体串扰的作用、细胞信号传导以及年龄的影响
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