PATHOGENESIS AND IN VIVO SUPPRESSION OF THIN FILAMENT-BASED CARDIOMYOPATHIES

细丝型心肌病的发病机制和体内抑制

基本信息

  • 批准号:
    10366554
  • 负责人:
  • 金额:
    $ 59.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-09-01 至 2026-12-31
  • 项目状态:
    未结题

项目摘要

Project Summary The thin filament is a multi-subunit regulatory machine. Proper regulation of cardiac contraction requires communication among, and controlled movement of, individual thin filament proteins. The goal of this application is to understand how post-translational modifications (PTMs) and human cardiomyopathy mutations, located at conserved interfaces between thin filament subunits, affect protein-protein associations, modulate muscle function, and/or lead to disease. Drosophila melanogaster benefits from robust experimental tools that permit efficient, yet comprehensive, scrutiny of the most proximal consequences of thin filament perturbations. This animal model will continue to help us discern the mechanistic basis of contractile regulation and, importantly, of myopathic responses to molecular insults. Mice, however, are more genetically and physiologically similar to humans. Using a unique combination of techniques including high-speed video and cryo-electron microscopy, in silico modeling, and mechanical assays we will define, for the first time, the structural and functional effects of specific PTMs and cardiomyopathy mutations, located at interfacial seams between thin filament subunits, from the molecular to the tissue level. Therefore, a highly integrative approach will be employed that relies, in part, on a pioneering strategy to express human actin variants in Drosophila for purification and biophysical analysis, and upon several new fly models of actin and troponin T (TnT)-based cardiomyopathies. The latter will be complemented by murine models. Aim 1 will focus on determining the effects of actin acetylation on tropomyosin (Tm) positioning and cardiac performance using recombinant human proteins, flies, and mice. We will test the hypothesis that acetylation of K326 and K328 on actin, residues we previously showed bind to and help orient Tm such that it prevents actomyosin cycling, discourages inhibitory Tm positioning and promotes cardiac contraction. For Aim 2 we will delineate how certain actin and TnT cardiomyopathy mutations uniquely affect myocardial relaxation. We will test the hypothesis that particular actin and TnT lesions disturb distinct, critical interfacial contacts with Tm, which differentially alters Tm-based inhibition of contraction and force production to initiate discrete cardiac pathologies. For Aim 3, we will ascertain if the same actin PTMs investigated in Aim 1, improve or worsen myocardial dysfunction in murine and fly cardiomyopathy models. We will test the hypothesis that enhanced cardiac contractility, conferred by actin pseudo-acetylation, will improve and aggravate the pathological phenotypes in models of dilated and hypertrophic cardiomyopathy, respectively. Overall, this work is significant since it will provide critical structural and functional information necessary to understand how the thin filament machine operates normally and during disease. Additionally, our efforts will yield genotype- phenotype information in a less complex model system (Drosophila) that limits genetic modifiers and environmental factors to help establish paradigms for disease processes involved in cardiac remodeling.
项目总结

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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Anthony Cammarato其他文献

Anthony Cammarato的其他文献

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{{ truncateString('Anthony Cammarato', 18)}}的其他基金

Pathogenesis and in vivo suppression of thin filament based cardiomyopathies
基于细丝的心肌病的发病机制和体内抑制
  • 批准号:
    9302507
  • 财政年份:
    2015
  • 资助金额:
    $ 59.5万
  • 项目类别:
Pathogenesis and in vivo suppression of thin filament based cardiomyopathies
基于细丝的心肌病的发病机制和体内抑制
  • 批准号:
    9065618
  • 财政年份:
    2015
  • 资助金额:
    $ 59.5万
  • 项目类别:
PATHOGENESIS AND IN VIVO SUPPRESSION OF THIN FILAMENT-BASED CARDIOMYOPATHIES
细丝型心肌病的发病机制和体内抑制
  • 批准号:
    10544001
  • 财政年份:
    2015
  • 资助金额:
    $ 59.5万
  • 项目类别:
Pathogenesis and in vivo suppression of thin filament based cardiomyopathies
基于细丝的心肌病的发病机制和体内抑制
  • 批准号:
    8884895
  • 财政年份:
    2015
  • 资助金额:
    $ 59.5万
  • 项目类别:
Pathogenesis and in vivo suppression of thin filament based cardiomyopathies
基于细丝的心肌病的发病机制和体内抑制
  • 批准号:
    8903521
  • 财政年份:
    2014
  • 资助金额:
    $ 59.5万
  • 项目类别:

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