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：
10831299
负责人：
ANTHONY ROSENZWEIG
金额：
$ 55.83万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10831299
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

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）是老年人发病率和死亡率的主要原因，目前代表旧住院的主要原因。高龄是HF的强大风险因素之一尽管为什么是这种情况以及是否可以干预此过程，但仍不清楚。在这个上下文，激活素II型受体（ACTRII）配体的作用及其在衰老和衰老中的潜在分解作用疾病 - 在HF中一直是引起人们强烈关注和争议的主题。我们有根本的差距了解衰老如何对HF做出贡献。我们的架构假设是Actrii激活增加随着年龄和生物力学心脏胁迫，并导致多种形式的心脏功能障碍与年龄有关的HF。我们的长期目标是了解将ACTRII信号连接到心脏的机制功能障碍并了解是否可以将这些途径用于治疗益处。目的当前的应用是检查在多个年龄相关模型中ACTRII信号的功能贡献 HF，并阐明基本机制。我们的初步数据表明ACTRII的活动人类人群中的途径随着年龄的增长，脆弱和HF而增加，并且小鼠的年龄和HF。增加活动主要通过活化素A而不是其他配体出现。在小鼠中，升高活化素A 水平足以引起心脏功能障碍，而在三种不同的HF模型中抑制途径防止或逆转HF。这些发现的翻译重要性是由目前正在试用其他适应症的途径抑制剂。拟议的工作将在三个集成的特定目的。在AIM 1中，我们将使用特定有效的功能障碍模型直接评估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AIM 2中，我们将阐明ACTRII导致心脏功能障碍的机制。在AIM 3中，我们将研究该途径的动态调节，该途径在老年患者的生物群样本中与蛋白质组学主管史蒂文·卡尔（Steven Carr）合作使用靶向质谱分析的失败在布罗德学院。相关临床数据的功能重要性将使用体内检查模型将通过体外研究主要心肌细胞来支持，以阐明基础机制。我们的方法结合了创新的假设，技术，独特的动物模型和相关临床人群中的翻译工作，拥有一支杰出团队的完整专业知识合作调查人员。拟议的研究很重要，因为预计它将推动我们的了解与年龄相关的HF和与衰老和疾病有关的描述途径减轻这些临床上重要的条件。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

lncExACT1 and DCHS2 Regulate Physiological and Pathological Cardiac Growth.

DOI：
10.1161/circulationaha.121.056850
发表时间：
2022-04-19
期刊：
CIRCULATION
影响因子：
37.8
作者：
Li, Haobo;Trager, Lena E.;Liu, Xiaojun;Hastings, Margaret H.;Xiao, Chunyang;Guerra, Justin;To, Samantha;Li, Guoping;Yeri, Ashish;Rodosthenous, Rodosthenis;Silverman, Michael G.;Das, Saumya;Ambardekar, Amrut V.;Bristow, Michael R.;Gonzalez-Rosa, Juan Manuel;Rosenzweig, Anthony
通讯作者：
Rosenzweig, Anthony

Animal Models of Exercise From Rodents to Pythons.

DOI：
10.1161/circresaha.122.320247
发表时间：
2022-06-10
期刊：
CIRCULATION RESEARCH
影响因子：
20.1
作者：
Hastings, Margaret H.;Herrera, Jonathan J.;Guseh, J. Sawalla;Atlason, Bjarni;Houstis, Nicholas E.;Abdul Kadir, Azrul;Li, Haobo;Sheffield, Cedric;Singh, Anand P.;Roh, Jason D.;Day, Sharlene M.;Rosenzweig, Anthony
通讯作者：
Rosenzweig, Anthony

Cardioprotective and Anti-Inflammatory Effects of FAM3D in Myocardial Ischemia-Reperfusion Injury.

FAM3D 在心肌缺血再灌注损伤中的心脏保护和抗炎作用。

DOI：
10.1161/circresaha.123.322640
发表时间：
2023
期刊：
Circulation research
影响因子：
20.1
作者：
Rhee,James;Freeman,Rebecca;Roh,Kangsan;Lyons,Margaret;Xiao,Chunyang;Zlotoff,Daniel;Yeri,Ashish;Li,Haobo;Guerra,Justin;Guseh,JSawalla;Kuznetsov,Alexandra;Houstis,Nicholas;Roh,Jason;Damilano,Federico;Liu,Xiaojun;Silverman,Mic
通讯作者：
Silverman,Mic

Exercise Training in Diabetes: Start Earlier or Exercise Harder.

DOI：
10.1161/circresaha.120.318219
发表时间：
2020-11-06
期刊：
Circulation research
影响因子：
20.1
作者：
Li H;Hastings MH;Rosenzweig A
通讯作者：
Rosenzweig A

CITED4 Protects Against Adverse Remodeling in Response to Physiological and Pathological Stress.

DOI：
10.1161/circresaha.119.315881
发表时间：
2020-08-14
期刊：
Circulation research
影响因子：
20.1
作者：
Lerchenmüller C;Rabolli CP;Yeri A;Kitchen R;Salvador AM;Liu LX;Ziegler O;Danielson K;Platt C;Shah R;Damilano F;Kundu P;Riechert E;Katus HA;Saffitz JE;Keshishian H;Carr SA;Bezzerides VJ;Das S;Rosenzweig A
通讯作者：
Rosenzweig A