Mechanistic Basis of Cardiac Laminopathy

心脏核纤层病的机制基础

基本信息

  • 批准号:
    10650433
  • 负责人:
  • 金额:
    $ 73.72万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-16 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Mutations in the lamin A/C gene (LMNA) encoding structural proteins of the nuclear lamina are responsible for up to ten percent of cases of inherited dilated cardiomyopathy. The disease is often referred to as cardiac laminopathy. Experimental evidence partially supports various pathogenic mechanisms of how defects in nuclear structural proteins cause cardiomyopathy, including that they lead to abnormalities in cell mechanical stability, dysregulation of gene expression and altered cell signaling. However, there is no unifying hypothesis integrating these defective processes and explaining exactly how they lead to cardiomyocyte damage and dysfunction. We recently found a surprising relationship between aberrant extracellular signal-regulated kinase 1/2 (ERK1/2) signaling and altered nuclear positioning in cardiac laminopathy. This has led us to hypothesize the existence of a mechanic checkpoint in which alterations in the nuclear lamina upregulate ERK1/2 activity, which causes mispositioning of the nucleus by phosphorylating and inactivating the actin bundling activity of the formin homology domain-containing protein (FHOD). Inactivation of FHOD prevents the linker of nucleoskeleton and cytoskeleton (LINC) complex, which spans the inner and outer nuclear membranes and connects to actin filaments, to mediate nuclear positioning. Normally, the mechanical checkpoint acts to prevent excessive force from being applied to the nucleus in contracting cardiomyocytes. However, with permanent alterations in nuclear structure resulting from LMNA mutations, the persistently activated checkpoint becomes maladaptive, resulting in abnormal nuclear positioning, nuclear envelope rupture, DNA damage and defects in sarcomere function. This Project is designed to prove the nuclear mechanical checkpoint hypothesis and determine its role in the pathogenesis of cardiac laminopathy. In Aim 1, we will examine how activation of the mechanical checkpoint for nuclear positioning alters cardiomyocyte biology. We will directly measure force on the nucleus using a nesprin- 2 actin tension sensor. As recent data suggest that the nucleus contributes to normal sarcomere, we will test the hypothesis that persistent mechanical checkpoint activation and nuclear mispositioning leads to defective sarcomere assembly and function in cardiomyocytes. In Aim 3, we will determine how altering the mechanical checkpoint affects the heart in vivo. We will test if expressing a phosphomimetic FOHD variant (checkpoint activation) in the heart induces cardiomyopathy in wild type mouse hearts and if a non-phosphorylatable variant (checkpoint inactivation) ameliorates pathology in a mouse model of cardiac laminopathy. Proving the existence of a novel nuclear mechanical checkpoint and establishing its role in the pathogenesis of cardiomyopathy caused by LMNA mutations will shift research directions in the field and potentially lead to new treatments for this life- threatening inherited heart disease.
项目总结

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Gregg G Gundersen其他文献

Gregg G Gundersen的其他文献

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{{ truncateString('Gregg G Gundersen', 18)}}的其他基金

Mechanistic Basis of Cardiac Laminopathy
心脏核纤层病的机制基础
  • 批准号:
    10279393
  • 财政年份:
    2021
  • 资助金额:
    $ 73.72万
  • 项目类别:
Cytoskeleton, Nucleus and Integrin Recycling in Cell Migration
细胞迁移中的细胞骨架、细胞核和整合素回收
  • 批准号:
    10396505
  • 财政年份:
    2020
  • 资助金额:
    $ 73.72万
  • 项目类别:
Cytoskeleton, Nucleus and Integrin Recycling in Cell Migration
细胞迁移中的细胞骨架、细胞核和整合素回收
  • 批准号:
    10613943
  • 财政年份:
    2020
  • 资助金额:
    $ 73.72万
  • 项目类别:
Cytoskeleton, Nucleus and Integrin Recycling in Cell Migration
细胞迁移中的细胞骨架、细胞核和整合素回收
  • 批准号:
    10799051
  • 财政年份:
    2020
  • 资助金额:
    $ 73.72万
  • 项目类别:
Nucleoskeleton-Cytoskeleton Connections and Cell Polarity in Aging
衰老过程中的核骨架-细胞骨架连接和细胞极性
  • 批准号:
    10289402
  • 财政年份:
    2019
  • 资助金额:
    $ 73.72万
  • 项目类别:
Nucleoskeleton-Cytoskeleton Connections and Cell Polarity in Aging
衰老过程中的核骨架-细胞骨架连接和细胞极性
  • 批准号:
    9982166
  • 财政年份:
    2019
  • 资助金额:
    $ 73.72万
  • 项目类别:
Nucleoskeleton-Cytoskeleton Connections and Cell Polarity in Aging
衰老过程中的核骨架-细胞骨架连接和细胞极性
  • 批准号:
    10153650
  • 财政年份:
    2019
  • 资助金额:
    $ 73.72万
  • 项目类别:
Nucleoskeleton-Cytoskeleton Connections and Cell Polarity in Aging
衰老过程中的核骨架-细胞骨架连接和细胞极性
  • 批准号:
    10394870
  • 财政年份:
    2019
  • 资助金额:
    $ 73.72万
  • 项目类别:
Integrin Recycling and Adhesion Formation in Cell Migration
细胞迁移中整合素的回收和粘附形成
  • 批准号:
    9765849
  • 财政年份:
    2019
  • 资助金额:
    $ 73.72万
  • 项目类别:
Nucleoskeleton-Cytoskeleton Connections and Cell Polarity in Aging
衰老过程中的核骨架-细胞骨架连接和细胞极性
  • 批准号:
    10619511
  • 财政年份:
    2019
  • 资助金额:
    $ 73.72万
  • 项目类别:

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