Project 2 (Bers)

项目2(Bers)

基本信息

  • 批准号:
    10249148
  • 负责人:
  • 金额:
    $ 74.77万
  • 依托单位:
  • 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:
    2019-09-01 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

Project 2 (Bers): Abstract Project 2 focuses on understanding Na- and Ca-dependent myocyte mechanisms contributing to cardiac dysfunction and arrhythmias in heart failure (HF). Hallmarks of Na & Ca dysfunction in HF include elevated diastolic and late Na current (INaL), increased diastolic SR Ca leak, and Na/Ca exchange. These factors reduce systolic and diastolic function and promote triggered arrhythmias in HF. Ca-Calmodulin dependent protein kinase (CaMKII) is also chronically active in HF and directly promotes INaL and diastolic SR Ca leak via the ryanodine receptor (RyR) and is a lynchpin in a newly appreciated vicious cycle where elevated INaL or SR Ca leak (that cause arrhythmias) promote CaMKII activation to further promote higher INaL and SR Ca leak that leads to both contractile dysfunction and arrhythmogenesis in HF. Our central aim is to test this working hypothesis in adult failing hearts (and computer models of human hearts) and identify how breaking the vicious cycle at different points can be functionally beneficial. Aim 1 will test in rabbit ventricular myocytes if functional and arrhythmogenic effects of overload-induced HF can be prevented by inhibiting CaMKII, INaL or RyR. Aim 2 extends these tests to the intact rabbit heart level using optical mapping of [Ca]i and voltage Vm (where whole heart arrhythmias are complicated by cell-cell coupling, source-sink mismatch and conduction/reentry issues). Aim 3 will enhance and validate computational rabbit ventricular myocyte & tissue models and extend both to human (using rabbit data from Aim 1 & 2 and incorporating patient-specific iPSC-derived myocyte and clinical data (from Projects 1 & 3). These 3 Aims will provide valuable mechanistic insight into the vicious feedback signaling, and how targeting INa, CaMKII or RyR may have benefits in acquired or inherited (Project 1) HF.
项目2 (Bers):摘要

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)

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Donald M Bers其他文献

The Difference of Calmodulin-Ryanodine Receptor Affinity Between N-terminal, Central and C-terminal RyR2-CPVT Knock-in Mice
N端、中央端和C端RyR2-CPVT敲入小鼠钙调蛋白-兰尼定受体亲和力的差异
  • DOI:
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Hitoshi Uchinoumi;Xiaoqiong Dong;Ivanita Stefanon;Mena Said;Rogerio Faustino;Razvan L Cornea;Univ of Minnesota;Xander H.t. Wehrens; Takeshi Yamamoto;Masafumi Yano;Donald M Bers
  • 通讯作者:
    Donald M Bers
Beyond beta blockers
超越β受体阻滞剂
  • DOI:
    10.1038/nm0405-379
  • 发表时间:
    2005-04-01
  • 期刊:
  • 影响因子:
    50.000
  • 作者:
    Donald M Bers
  • 通讯作者:
    Donald M Bers

Donald M Bers的其他文献

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{{ truncateString('Donald M Bers', 18)}}的其他基金

Training Program in Pharmacology
药理学培训计划
  • 批准号:
    10656570
  • 财政年份:
    2022
  • 资助金额:
    $ 74.77万
  • 项目类别:
Systems Approach to Understanding Cardiovascular Disease and Arrhythmias - Cell diversity in the cardiovascular system, cell-autonomous and cell-cell signaling
了解心血管疾病和心律失常的系统方法 - 心血管系统中的细胞多样性、细胞自主和细胞间信号传导
  • 批准号:
    10386681
  • 财政年份:
    2021
  • 资助金额:
    $ 74.77万
  • 项目类别:
Systems Approach to Understanding Cardiac Arrhythmias Mechanisms
了解心律失常机制的系统方法
  • 批准号:
    9763307
  • 财政年份:
    2019
  • 资助金额:
    $ 74.77万
  • 项目类别:
Project 2 (Bers)
项目2(Bers)
  • 批准号:
    10677715
  • 财政年份:
    2019
  • 资助金额:
    $ 74.77万
  • 项目类别:
Project 2 (Bers)
项目2(Bers)
  • 批准号:
    10006341
  • 财政年份:
    2019
  • 资助金额:
    $ 74.77万
  • 项目类别:
Modelling structural and functional heterogeneity in heart failure reveals arrhythmic impact
心力衰竭的结构和功能异质性建模揭示了心律失常的影响
  • 批准号:
    10199780
  • 财政年份:
    2019
  • 资助金额:
    $ 74.77万
  • 项目类别:
Modelling structural and functional heterogeneity in heart failure reveals arrhythmic impact
心力衰竭的结构和功能异质性建模揭示了心律失常的影响
  • 批准号:
    10449125
  • 财政年份:
    2019
  • 资助金额:
    $ 74.77万
  • 项目类别:
Project 2 (Bers)
项目2(Bers)
  • 批准号:
    10471339
  • 财政年份:
    2019
  • 资助金额:
    $ 74.77万
  • 项目类别:
CaMKII activation and regulation in adult cardiac myocytes
成人心肌细胞中 CaMKII 的激活和调节
  • 批准号:
    10687251
  • 财政年份:
    2018
  • 资助金额:
    $ 74.77万
  • 项目类别:
High-Throughput Screens to Discover Novel Inhibitors of Leaky RyR2 for Heart Failure Therapy
高通量筛选发现用于心力衰竭治疗的漏性 RyR2 新型抑制剂
  • 批准号:
    10064096
  • 财政年份:
    2018
  • 资助金额:
    $ 74.77万
  • 项目类别:

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肾上腺素能药物治疗AD疗效的临床前试验
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