Role of Activin Type II receptor signaling in age-related heart failure

心力衰竭（HF）是老年人发病和死亡的主要原因，目前代表 是老年人住院的主要原因。高龄是心力衰竭的最强危险因素之一， 但为什么会出现这种情况以及是否有可能干预这一过程仍不清楚。在这个 激活素 II 型受体 (ActRII) 配体的作用及其在衰老和衰老过程中的潜在分解代谢作用 疾病——一直是心力衰竭引起人们强烈兴趣和争议的话题。我们之间存在着根本性的差距 了解衰老如何导致心力衰竭。我们的首要假设是 ActRII 激活增加 随着年龄和生物力学心脏应激，并导致多种形式的心脏功能障碍 与年龄相关的心力衰竭。我们的长期目标是了解 ActRII 信号传导与心脏的联系机制 功能障碍并了解这些途径是否可以作为治疗益处的目标。该计划的目标 目前的应用是检查 ActRII 信号在多种年龄相关模型中的功能贡献 HF，并阐明其潜在机制。我们的初步数据表明 ActRII 的活动 在人类群体中，该通路随着年龄、虚弱和心力衰竭而增加，而在小鼠中，则随着年龄和心力衰竭而增加。增加的 活性似乎主要由激活素 A 而不是其他配体驱动。在小鼠中，激活素 A 升高 水平足以引起心脏功能障碍，而在三种不同的心力衰竭模型中抑制该通路 预防或逆转心力衰竭。这些发现的转化重要性因以下因素的存在而得到强调： 途径抑制剂目前正在针对其他适应症进行试验。拟议的工作将分三期进行 综合具体目标。在目标 1 中，我们将使用具体且有效的功能获得和丧失模型来 直接评估 ActRII 信号在 HF 中的作用，并检查 ActRII 在体内心肌细胞中的作用。 在目标 2 中，我们将阐明 ActRII 导致心脏功能障碍的机制。在目标 3 中，我们将 研究老年心脏病患者生物库样本中该通路的动态调节 与蛋白质组学主任 Steven Carr 博士合作使用靶向质谱分析失败 在布罗德研究所。将使用体内检查相关临床数据的功能重要性 模型，这将得到原代心肌细胞体外研究的支持，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 通过优秀团队的互补专业知识，在相关临床人群中开展转化工作 合作调查人员。拟议的研究意义重大，因为它有望推进我们的研究 了解与年龄相关的心力衰竭并描绘与衰老和疾病相关的途径，有可能 减轻这些临床上重要的情况。

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.