The role of CAP2 in sex-related myocardial function

CAP2在性别相关心肌功能中的作用

基本信息

批准号：
9216795
负责人：
JEFFREY M FIELD
金额：
$ 40.25万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-12 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9216795
关键词：
6p22 Actins Adenylate Cyclase Affect American Animals Attenuated Binding Proteins Birth Cardiac Cardiac Death Cardiac Myocytes Cardiac conduction system Cardiomyopathies Chromosomes, Human, Pair 6 Coronary Arteriosclerosis Cytoskeletal Proteins Cytoskeleton Data Dilated Cardiomyopathy Disease Electrophysiology (science)Enterobacteria phage P1 Cre recombinase Equilibrium Female Fibrosis Gender Genes Genetic Transcription Heart Heart Arrest Heart Block Heart failure Histologic Hormonal Intraventricular Ion Channel Knock-out Knockout Mice Link Mammals Microfilaments Modeling Mus Mutation Myocardial Myocardium Outcome Pathology Pathway interactions Patients Phenotype Protein Isoforms Proteins Risk Role Sarcomeres Serum Response Factor Sex Bias Sex Characteristics Signal Transduction Specificity Structure Sudden Death System Techniques Testing Time Woman Yeasts base disease-causing mutation experience genome-wide analysis high risk improved in vivo inhibitor/antagonist killings knockout animal male men monomer mouse model response screening sex sudden cardiac death transcriptome

项目摘要

Summary Sudden cardiac death kills 180,000 to 450,000 Americans annually. In patients without coronary artery disease, the highest risk of sudden death is in those with cardiomyopathy and intraventricular conduction delay. Furthermore, males experience sudden death almost three times more frequently than females and the reasons for this sex bias are unclear. Identifying the mechanisms underlying cardiomyopathy and conduction disorders may improve screening for patients at risk for sudden death, or outcomes of those revived from cardiac arrest. To date, most known mutations that cause cardiomyopathy are in sarcomere cytoskeletal proteins whereas most familial cardiac conduction diseases (CCD) are caused by mutations in ion channels or channel interacting proteins. However, mutations in cytoskeletal proteins can also cause CCD but the mechanisms linking the cytoskeleton to CCD are not well understood. There is a gene or genes on chromosome 6 (6p22) associated with sudden cardiac death near the cytoskeletal protein CAP2 (Cyclase Associated Protein 2). CAPs are widely conserved cytoskeleton proteins. We first identified CAP in yeast as an adenylyl cyclase binding protein. Additionally, all CAP homologs are actin monomer binding proteins that regulate the balance between actin filaments and actin monomers. Mammals have two CAP isoforms, CAP1 and CAP2. To determine the function of CAP2 in vivo we generated CAP2 knockout (CAP2-KO) mice, both whole body and conditional. Our preliminary data show that whole body CAP2-KO mice are born alive, but many die suddenly shortly after birth, with only ~30% of male CAP2-KO surviving beyond 12 weeks. CAP2-KO mice develop CCD with mild dilated cardiomyopathy (DCM). The conduction phenotypes are more penetrant in cardiomyocyte-specific CAP2-KO mice, with all mice dying of complete heart block by 25 weeks. Furthermore, genome-wide analysis revealed that several transcriptional networks, including the serum response factor (SRF) network, were upregulated in the hearts of CAP2-KO mice. Based on these findings we hypothesize CAP2 maintains cardiac conduction by modulating SRF signals and fibrotic responses in a sex-specific manner. These studies are relevant to understanding the role of the cytoskeleton and gender specificity in cardiac conduction and sudden cardiac death. To test this hypothesis, we propose the following specific aims: To test this hypothesis, we propose to (1) Determine the specific role of CAP2 in the cardiac conduction system (2) Determine the role of CAP2 in serum response factor (SRF) signaling, and (3) Determine the role of Secreted Frizzled-related protein 2 in sex-specific sudden cardiac death in CAP2 mice.

概括每年有 18 万至 45 万美国人死于心源性猝死。无冠状动脉的患者猝死的风险最高的是那些患有心肌病和心室内疾病的人传导延迟。此外，男性猝死的频率几乎是男性的三倍性别偏见的原因尚不清楚。确定潜在机制心肌病和传导障碍可以改善对有猝死风险的患者的筛查，或那些从心脏骤停中复苏的人的结果。迄今为止，大多数已知的突变导致心肌病存在于肌节细胞骨架蛋白中，而大多数家族性心脏传导疾病（CCD）是由离子通道或通道相互作用蛋白的突变引起的。然而，细胞骨架蛋白的突变也可能导致 CCD，但将细胞骨架与细胞骨架连接起来的机制 CCD不太了解。 6 号染色体 (6p22) 上有一个或多个基因与细胞骨架蛋白 CAP2（环化酶相关蛋白 2）附近的心脏性猝死。 CAP 是广泛保守的细胞骨架蛋白。我们首先将酵母中的 CAP 鉴定为腺苷酸环化酶结合蛋白质。此外，所有 CAP 同源物都是肌动蛋白单体结合蛋白，可调节平衡肌动蛋白丝和肌动蛋白单体之间。哺乳动物有两种 CAP 亚型：CAP1 和 CAP2。到为了确定 CAP2 的体内功能，我们生成了 CAP2 敲除 (CAP2-KO) 小鼠，均为完整小鼠身体和条件。我们的初步数据显示全身CAP2-KO小鼠出生时是活的，但是许多人在出生后不久就突然死亡，只有约 30% 的男性 CAP2-KO 存活超过 12 周。 CAP2-KO 小鼠出现 CCD 并伴有轻度扩张型心肌病 (DCM)。传导表型是在心肌细胞特异性 CAP2-KO 小鼠中渗透性更强，所有小鼠均死于完全性心脏传导阻滞到 25 周。此外，全基因组分析揭示了几个转录网络，包括血清反应因子 (SRF) 网络在内的 CAP2-KO 小鼠心脏中的表达上调。基于这些发现，我们假设 CAP2 通过调节来维持心脏传导 SRF 以性别特异性方式发出信号和纤维化反应。这些研究涉及了解细胞骨架和性别特异性在心脏传导和突发性心脏病中的作用心源性死亡。为了检验这一假设，我们提出以下具体目标：为了检验这一假设，我们建议 (1) 确定 CAP2 在心脏功能中的具体作用传导系统 (2) 确定 CAP2 在血清反应因子 (SRF) 信号传导中的作用，以及 (3) 确定分泌型卷曲相关蛋白 2 在 CAP2 性别特异性心源性猝死中的作用老鼠。