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

基本信息

  • 批准号:
    9302507
  • 负责人:
  • 金额:
    $ 41.47万
  • 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 2019-06-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Striated muscle contraction involves highly dynamic processes that require coordinated communication among, and relative movement of, individual thin filament components. The goal of this application is to understand how human cardiomyopathy mutations located at conserved interfaces between thin filament subunits lead to disease. Drosophila melanogaster, the fruit fly, benefits from robust experimental tools that permit efficient tissue-specific expression of disease alleles in cardiac or skeletal muscle and relatively rapid genetic interaction screens. The fly represents a powerful in vivo system to scrutinize the most proximal consequences of thin filament lesions to facilitate our effort to discern the molecular basis of contractile regulation and, importantly, of myopathic responses in humans. A remarkably integrative approach will be employed that relies upon several new Drosophila models of actin and troponin T (TnT)-based cardiomyopathies. Animal models do not currently exist for five of the six mutations under investigation here, minimizing our comprehension of the pathological effects of these disease alleles in the physiological context of muscle. Using a unique combination of imaging techniques that includes high-speed live video, confocal, atomic force and electron microscopy we will define, for the first time, the structural and functional effects of the cardiomyopathy mutations from the tissue to the molecular level. The studies will involve pioneering strategies to evaluate Drosophila systolic and diastolic molecular mechanics in vivo. Aim 1 will focus on multiple hypertrophic cardiomyopathy (HCM) models that express one of three a-cardiac actin missense mutations. We will test the hypothesis that the HCM actin variants induce similar cardiac and skeletal pathology in flies due to equivalently disturbed tropomyosin (Tm)-based contractile regulation that leads to excessive contractile activity. For Aim 2 the hierarchical effects of several TnT cardiomyopathy mutations will be delineated. We will test the hypothesis that the mutations differentially influence TnT-Tm interaction, which distinctly affects the extent of contractile inhibition and consequently prompts diverse cardiac remodeling in flies. For Aim 3 "second-site" actin mutations will be used to improve cardiac dysfunction initiated by aberrant TnT, in vivo and in vitro. Using Drosophila we identified specific actin lesions that suppress TnT-mediated skeletal myopathy. We will now test the hypothesis that, when co-expressed, these second-site actin mutations can ameliorate TnT-based cardiomyopathies in our fly models. Overall this work is significant since it will provide critical structural-functional information necessary to better comprehend how the thin filament machine functions normally and during disease. Additionally, our efforts will yield genotype-phenotype information in a less complex model system that limits genetic modifiers and environmental factors to help establish paradigms and treatment strategies for pathological processes involved in cardiac remodeling.


项目成果

期刊论文数量(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:
    9065618
  • 财政年份:
    2015
  • 资助金额:
    $ 41.47万
  • 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:
    10366554
  • 财政年份:
    2015
  • 资助金额:
    $ 41.47万
  • 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:
    $ 41.47万
  • 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:
    $ 41.47万
  • 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:
    $ 41.47万
  • 项目类别:

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