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)是老年人发病率和死亡率的主要原因，目前 老年人住院的主要原因。高龄是心力衰竭的最大危险因素之一， 尽管为什么会出现这种情况，以及是否有可能干预这一过程，但仍不清楚。在这 背景，激活素II型受体(ActRII)配体的作用-及其在衰老和衰老中潜在的分解代谢作用 疾病--在心力衰竭中一直是一个引起强烈兴趣和争议的话题。我们有一个根本性的差距 了解衰老是如何导致心衰的。我们的总体假设是ActRII激活增加 与年龄和生物力学心脏应激有关，并在多种形式的心脏功能障碍中起作用 年龄相关性心力衰竭。我们的长期目标是了解ActRII信号与心脏 并了解这些通路是否可以作为治疗的靶点。该计划的目标是 目前的应用是研究ActRII信号在多种年龄相关模型中的功能贡献 并阐明其潜在的机制。我们的初步数据显示ActRII的活动 在人类队列中，路径随着年龄、虚弱和HF而增加，在小鼠中，随着年龄和HF的增加而增加。增加的 活性似乎主要由激活素-A驱动，而不是其他配体。在小鼠中，升高激活素-A 在三种不同的心力衰竭模型中，水平足以导致心功能障碍，而该途径受到抑制 防止或逆转心力衰竭。这些发现的翻译重要性因存在于 途径抑制剂目前正在试验其他适应症。拟议的工作将分三个阶段进行 综合的具体目标。在目标1中，我们将使用具体和有效的功能增益和损耗模型来 直接评估ActRII信号在心衰中的作用，并检测ActRII在活体心肌细胞中的作用。 在目标2中，我们将阐明ActRII导致心功能不全的机制(S)。在《目标3》中，我们将 老年心脏病人生物库标本中这一途径的动态调节 与蛋白质组学主任Steven Carr博士合作使用靶向质谱分析失败 在布罗德学院。相关临床数据的功能重要性将在体内进行检验 模型，这将支持对原代心肌细胞的体外研究，以阐明潜在的 机制。我们的方法结合了创新的假设、技术、独特的动物模型和 在相关临床人群中进行翻译工作，并与一支优秀的 合作的调查员。这项拟议的研究意义重大，因为它有望推动我们的 了解与年龄相关的心衰，并描述与衰老和疾病相关的途径，有可能 缓解这些临床上重要的疾病。