Cardiac Myocyte Protein Partners in Heart Function

心肌细胞蛋白在心脏功能中的伙伴

基本信息

  • 批准号:
    10502152
  • 负责人:
  • 金额:
    $ 73.28万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-18 至 2026-04-30
  • 项目状态:
    未结题

项目摘要

Cardiomyopathy (CMY) is a worldwide problem associated with high morbidity and mortality. CMY patients may present with symptoms attributed to heart failure (HF), arrhythmias, cardiac conduction system abnormalities, and sudden cardiac death. Recently it has been increasingly recognized that genetic screening for etiologies of CMY is important, and that defects in cardiomyocyte (CM) proteins in cellular junctions can cause CMY. Mechanical and electrical coupling of CM occurs at the intercellular connection between CM, termed the intercalated disk (ID). The ID provides essential properties to allow the heart to function as a syncytium. Structural elements of the cardiac conduction system (CCS) such as the atrioventricular (AV) and sinoatrial (SA) nodes have cellular arrangements and intercellular connections that vary from working CMs in the atrium and ventricle. Understanding more about proteins essential for normal function of working CMs and CCS cells is critical to advance our knowledge of the basis of cardiac disease, and remains understudied. This proposal is focused on Vinculin (VCL) and Zonula Occludens (ZO) proteins, which bind directly to one another, are located in the ID and the lateral membrane of working CMs and have known links to human disease. Our global hypothesis here is that VCL, ZO-1 and ZO-2 have unique roles in preserving cardiac function, conduction, and rhythm, given their location in CMs and in the CCS. We propose two aims. AIM 1 will evaluate how loss of ZO and VCL proteins from CMs alters contractile function and the molecular phenotype of the working CM and adult heart. We hypothesize that with postnatal loss of CM ZO and VCL proteins, cell-cell communication and integrity of the working myocardium will be disturbed, resulting in contractile dysfunction. CM ZO loss is expected to be distinct from that caused by loss of CM VCL, despite these proteins directly binding one another. Unique mouse models in hand will be used to evaluate the effects of loss of ZO and VCL from mature CMs basally and after the heart is faced with stress. We will assess whole heart, tissue and single cells using physiological, biochemical, and microscopic evaluations, as well as a novel approach to single cell transcriptomics and single cell proteomics, to pursue the mechanistic basis for how ZO and VCL protein loss causes CMY. Differences by sex and in atria vs. ventricle will be considered. AIM 2 will determine the function of ZO-1 and VCL in cardiac conduction and rhythm. Deletion of VCL from CM caused ventricular arrhythmias and sudden death, while loss of CM ZO-1 produced CCS dysfunction. We hypothesize that these two proteins have unique roles in controlling cardiac rhythm and conduction, despite their direct binding, due to interactions with connexins and membrane ion channels. Using patch clamping, high-resolution confocal microscopy to detect Ca2+ transients, optical voltage/Ca2+ mapping, and single cell transcriptional and proteomic studies, we will test how loss of ZO-1 leads to altered SAN and AVN function and excitation-contraction coupling, and how loss of VCL leads to ventricular arrhythmias and sudden death.
心肌病(CMY)是一个与高发病率和死亡率相关的世界性问题。 CMY 患者可能 出现心力衰竭(HF)、心律失常、心脏传导系统异常的症状, 和心源性猝死。近年来,人们越来越认识到,对疾病病因进行基因筛查 CMY 很重要,细胞连接处心肌细胞 (CM) 蛋白的缺陷会导致 CMY。 CM 的机械和电耦合发生在 CM 之间的细胞间连接处,称为 闰盘(ID)。 ID 提供了使心脏发挥合胞体功能的基本特性。结构性 心脏传导系统 (CCS) 的元件,例如房室 (AV) 和窦房 (SA) 结 其细胞排列和细胞间连接与心房和心室中工作的 CM 不同。 了解更多关于工作 CM 和 CCS 细胞正常功能所必需的蛋白质对于 提高了我们对心脏病基础的认识,并且仍在研究中。 该提案的重点是粘蛋白 (VCL) 和闭锁带 (ZO) 蛋白,它们直接结合 彼此之间,位于工作 CM 的 ID 和侧膜中,并且已知与 人类疾病。我们的总体假设是 VCL、ZO-1 和 ZO-2 在保护心脏方面具有独特的作用 功能、传导和节律,考虑到它们在 CM 和 CCS 中的位置。我们提出两个目标。 AIM 1 将评估 CM 中 ZO 和 VCL 蛋白的丢失如何改变收缩功能以及 工作 CM 和成人心脏的分子表型。我们假设出生后 CM ZO 丢失 和 VCL 蛋白,细胞间通讯和工作心肌的完整性将受到干扰,导致 收缩功能障碍。 CM ZO 损失预计与 CM VCL 损失造成的损失不同,尽管有这些 蛋白质之间直接结合。现有的独特小鼠模型将用于评估损失的影响 基础上和心脏面临压力后,来自成熟CM的ZO和VCL。我们将全心评估, 使用生理、生化和显微镜评估对组织和单细胞进行评估,以及一种新颖的方法 单细胞转录组学和单细胞蛋白质组学方法,探索 ZO 的机制基础 VCL蛋白丢失导致CMY。将考虑性别以及心房与心室的差异。 AIM 2 将确定 ZO-1 和 VCL 在心脏传导和节律中的功能。删除VCL CM 引起室性心律失常和猝死,而 CM ZO-1 的缺失则导致 CCS 功能障碍。 我们假设这两种蛋白质在控制心律和传导方面具有独特的作用, 尽管它们是直接结合的,但由于与连接蛋白和膜离子通道的相互作用。使用补丁 钳位、高分辨率共焦显微镜检测 Ca2+ 瞬变、光学电压/Ca2+ 映射和单 细胞转录和蛋白质组学研究,我们将测试 ZO-1 的缺失如何导致 SAN 和 AVN 功能改变 和兴奋-收缩耦合,以及 VCL 的缺失如何导致室性心律失常和猝死。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Joshua I Goldhaber其他文献

Joshua I Goldhaber的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Joshua I Goldhaber', 18)}}的其他基金

Cardiac Myocyte Protein Partners in Heart Function
心肌细胞蛋白在心脏功能中的伙伴
  • 批准号:
    10667626
  • 财政年份:
    2022
  • 资助金额:
    $ 73.28万
  • 项目类别:
Regulation of cellular calcium by cardiac sodium-calcium exchange
通过心脏钠钙交换调节细胞钙
  • 批准号:
    9906764
  • 财政年份:
    2019
  • 资助金额:
    $ 73.28万
  • 项目类别:
Regulation of cellular calcium by cardiac sodium-calcium exchange
通过心脏钠钙交换调节细胞钙
  • 批准号:
    10376807
  • 财政年份:
    2019
  • 资助金额:
    $ 73.28万
  • 项目类别:
Regulation of cellular calcium by cardiac sodium-calcium exchange
通过心脏钠钙交换调节细胞钙
  • 批准号:
    9766112
  • 财政年份:
    2019
  • 资助金额:
    $ 73.28万
  • 项目类别:
Training in Advanced Heart Disease Research
高级心脏病研究培训
  • 批准号:
    10556039
  • 财政年份:
    2013
  • 资助金额:
    $ 73.28万
  • 项目类别:
Training in Advanced Heart Disease Research
高级心脏病研究培训
  • 批准号:
    8703767
  • 财政年份:
    2013
  • 资助金额:
    $ 73.28万
  • 项目类别:
Training in Advanced Heart Disease Research
高级心脏病研究培训
  • 批准号:
    10250485
  • 财政年份:
    2013
  • 资助金额:
    $ 73.28万
  • 项目类别:
Training in Advanced Heart Disease Research
高级心脏病研究培训
  • 批准号:
    10442623
  • 财政年份:
    2013
  • 资助金额:
    $ 73.28万
  • 项目类别:
Training in Advanced Heart Disease Research
高级心脏病研究培训
  • 批准号:
    10000201
  • 财政年份:
    2013
  • 资助金额:
    $ 73.28万
  • 项目类别:
Training in Advanced Heart Disease Research
高级心脏病研究培训
  • 批准号:
    8550586
  • 财政年份:
    2013
  • 资助金额:
    $ 73.28万
  • 项目类别:

相似海外基金

Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
  • 批准号:
    MR/Z503605/1
  • 财政年份:
    2024
  • 资助金额:
    $ 73.28万
  • 项目类别:
    Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
  • 批准号:
    2336167
  • 财政年份:
    2024
  • 资助金额:
    $ 73.28万
  • 项目类别:
    Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
  • 批准号:
    2402691
  • 财政年份:
    2024
  • 资助金额:
    $ 73.28万
  • 项目类别:
    Standard Grant
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
  • 批准号:
    2341428
  • 财政年份:
    2024
  • 资助金额:
    $ 73.28万
  • 项目类别:
    Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
  • 批准号:
    24K12150
  • 财政年份:
    2024
  • 资助金额:
    $ 73.28万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
  • 批准号:
    DE240100561
  • 财政年份:
    2024
  • 资助金额:
    $ 73.28万
  • 项目类别:
    Discovery Early Career Researcher Award
RUI: Evaluation of Neurotrophic-Like properties of Spaetzle-Toll Signaling in the Developing and Adult Cricket CNS
RUI:评估发育中和成年蟋蟀中枢神经系统中 Spaetzle-Toll 信号传导的神经营养样特性
  • 批准号:
    2230829
  • 财政年份:
    2023
  • 资助金额:
    $ 73.28万
  • 项目类别:
    Standard Grant
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
  • 批准号:
    23K09542
  • 财政年份:
    2023
  • 资助金额:
    $ 73.28万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
  • 批准号:
    23K07552
  • 财政年份:
    2023
  • 资助金额:
    $ 73.28万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
  • 批准号:
    23K07559
  • 财政年份:
    2023
  • 资助金额:
    $ 73.28万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了