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: 10540381
• 负责人: ANTHONY ROSENZWEIG
• 金额: --
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10540381
• 关键词: Activins; Acute; Age; Aging; Animal Model; Aortic Valve Stenosis; Binding; Biological Assay; Biology; Biomechanics; Bone Morphogenetic Proteins; Calcium; Cardiac; Cardiac Myocytes; Clinical; Clinical Data; Clinical Research; Collaborations; Complex; Conflict (Psychology); Coupling; Data; Development; Disease; Elderly; FSTL3 gene; Foundations; Future; GDF11 gene; GDF8 gene; Genetic; Goals; Growth Factor; Health; Heart failure; Hospitalization; Human; In Vitro; Investigation; Knowledge; Learning; Ligands; Link; Mass Spectrum Analysis; Measurement; Methods; Mission; Modeling; Morbidity - disease rate; Mus; Myocardial dysfunction; Myopathy; Outcome; Pathway interactions; Patients; Peptides; Phenotype; Population; Post-Translational Protein Processing; Prevalence; Process; Protein Family; Protein Isoforms; Proteins; Proteomics; Public Health; Publishing; Receptor Activation; Receptor Signaling; Regulation; Reporting; Research; Research Personnel; Risk Factors; Role; SERCA2a; Sampling; Skeletal Muscle; Stress; Technology; Type II Activin Receptors; United States National Institutes of Health; Work; activin A; age related; biobank; cell type; clinical development; clinically relevant; cohort; frailty; gain of function; in vivo; in vivo Model; inhibitor; innovation; insight; interest; loss of function; morphogens; mortality; mouse model; multiple reaction monitoring; older patient; pharmacologic; pressure; prevent; targeted treatment; therapeutic target; valve replacement

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