A Model Multi-systems Approach for Understanding the Role of the PIX Pathway in Cardiac Muscle and Cardiomyopathy

理解 PIX 通路在心肌和心肌病中作用的模型多系统方法

基本信息

  • 批准号:
    10532707
  • 负责人:
  • 金额:
    $ 57.56万
  • 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:
    2022-01-01 至 2025-12-31
  • 项目状态:
    未结题

项目摘要

Myofibrils located at the periphery of the muscle cell are attached to the sarcolemma via costameres, muscle- specific integrin adhesion complexes (IACs), that transmit the force of muscle contraction to the outside of the cell. IACs consist of the transmembrane protein integrin and hundreds of proteins in a complex both in the ECM and especially intracellularly. Although much is known about the composition of IACs and mechanisms that initiate their assembly, we do not know how the composition of an IAC is determined, and what determines where an IAC will form. We exploit the conservation of muscle structure/function and the power of genetics in C. elegans. From a genetic screen, we identified a gene, pix-1, which is required for the formation of IACs at muscle cell boundaries (MCBs), but not the other IACs (M-lines and dense bodies). PIX-1 is the nematode ortholog of human b-PIX, which contains a RhoGEF domain known to be an activator of Rac1 and Cdc42. pix- 1 mutants show decreased whole animal locomotion. As compared to wild type, a pix-1 null mutant, shows 50% reduction in the level of activated (GTP bound) Rac in muscle. In addition to deficiency of PIX-1, overexpression of wild type PIX-1 protein results in decreased locomotion and disrupted MCBs. PIX-1 localizes to all 3 IACs in muscle—M-lines, dense bodies and MCBs. Loss of function mutants in each of the known PIX pathway proteins (PIX, Rac, GIT) result in disrupted MCBs. The protein kinase activity of PAK-1 is essential for its MCB function: a kinase-dead PAK-1 mutant has disrupted MCBs. Although PIX proteins are known to be important in several cell types in mammals and nematodes, our results are the first to demonstrate that a PIX protein is required for assembly of an IAC, and is required in striated muscle. A GAP protein (inactivates Rac) for this pathway has not been reported for any cell type or organism, but we now have two candidate GAPs. Remarkably, we found that heart specific knockout of the mouse ortholog b-PIX results in dilated cardiomyopathy at 8 months of age. Similarly, heart-specific knockdown of the Drosophila ortholog, dPix, also results in cardiomyopathy. We hypothesize that PIX proteins, through their RacGEF activity, direct assembly of IACs by activating PAK kinases to phosphorylate key substrate(s) in muscle. We will leverage the unique advantages of 3 model systems to learn new conserved functions of the PIX pathway in striated and cardiac muscle. Aim 1: Exploiting the power of studying muscle in C. elegans we will: (a) identify the GAP protein(s); (b) determine the localization, function and substrates of PAK kinases, and (c) test the hypothesis that PIX-1 is only required at MCBs because there are additional RacGEF proteins at the other IAC locations. Aim 2: We will determine how b-PIX functions in the mouse heart and how its absence leads to cardiomyopathy. Aim 3: We will take advantage of the power of genetic modifier screens in Drosophila to identify new members of the PIX pathway in muscle, and more specifically, cardiac muscle. There is a need to identify additional cardiomyopathy genes in humans and genes encoding members of the PIX pathway may be new candidates.
肌原纤维位于肌细胞的外围,通过肋肌、肌膜与肌膜相连

项目成果

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GUY Martin BENIAN其他文献

GUY Martin BENIAN的其他文献

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{{ truncateString('GUY Martin BENIAN', 18)}}的其他基金

A Model Multi-systems Approach for Understanding the Role of the PIX Pathway in Cardiac Muscle and Cardiomyopathy
理解 PIX 通路在心肌和心肌病中作用的模型多系统方法
  • 批准号:
    10340546
  • 财政年份:
    2022
  • 资助金额:
    $ 57.56万
  • 项目类别:
ApoE4 and C/EBP: Mutually Regulate Each Other in Alzheimer's Disease
ApoE4 和 C/EBP:在阿尔茨海默病中相互调节
  • 批准号:
    10319519
  • 财政年份:
    2020
  • 资助金额:
    $ 57.56万
  • 项目类别:
ApoE4 and C/EBP: Mutually Regulate Each Other in Alzheimer's Disease
ApoE4 和 C/EBP:在阿尔茨海默病中相互调节
  • 批准号:
    10533321
  • 财政年份:
    2020
  • 资助金额:
    $ 57.56万
  • 项目类别:
The UNC-45 Chaperone as a Modulator of Myosin Biogenesis and Function
UNC-45 伴侣作为肌球蛋白生物发生和功能的调节剂
  • 批准号:
    9267166
  • 财政年份:
    2016
  • 资助金额:
    $ 57.56万
  • 项目类别:
The UNC-45 Chaperone as a Modulator of Myosin Biogenesis and Function
UNC-45 伴侣作为肌球蛋白生物发生和功能的调节剂
  • 批准号:
    9477067
  • 财政年份:
    2016
  • 资助金额:
    $ 57.56万
  • 项目类别:
The UNC-45 Chaperone as a Modulator of Myosin Biogenesis and Function
UNC-45 伴侣作为肌球蛋白生物合成和功能的调节剂
  • 批准号:
    9789043
  • 财政年份:
    2016
  • 资助金额:
    $ 57.56万
  • 项目类别:
Role of UNC-89 (obscurin) in sarcomere assembly and maintenance.
UNC-89(obscurin)在肌节组装和维护中的作用。
  • 批准号:
    8836489
  • 财政年份:
    2014
  • 资助金额:
    $ 57.56万
  • 项目类别:
Role of UNC-89 (obscurin) in sarcomere assembly and maintenance.
UNC-89(obscurin)在肌节组装和维护中的作用。
  • 批准号:
    8632004
  • 财政年份:
    2014
  • 资助金额:
    $ 57.56万
  • 项目类别:
Using C. elegans to study titin and obscurin (UNC-89)
使用线虫研究 titin 和 obscurin (UNC-89)
  • 批准号:
    7847206
  • 财政年份:
    2009
  • 资助金额:
    $ 57.56万
  • 项目类别:
Nematode UNC-98 functions in focal adhensions and nuclei
线虫 UNC-98 在粘着点和细胞核中发挥作用
  • 批准号:
    6968518
  • 财政年份:
    2005
  • 资助金额:
    $ 57.56万
  • 项目类别:
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