Nuclear mechanics and mechanotransduction in muscular laminopathies

肌肉核纤层蛋白病的核力学和机械转导

• 批准号: 8413555
• 负责人: Jan Lammerding
• 金额: $ 7.94万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413555
• 关键词: Nuclear; mechanics; mechanotransduction; muscular; laminopathies

DESCRIPTION (provided by applicant): The nucleus is the distinguishing feature of eukaryotic cells and is separated from the surrounding cytoplasm by the nuclear envelope. Mutations in the nuclear envelope proteins lamin A/C and emerin cause Emery- Dreifuss muscular dystrophy, limb-girdle muscular dystrophy, familial partial lipodystrophy, and a variety of other diseases referred to as laminopathies. The underlying disease mechanism is unclear, in part because the function of the nuclear envelope proteins is incompletely defined. My long term goal is to understand the molecular mechanism(s) by which mutations in these ubiquitously expressed proteins can lead to such tissue-specific phenotypes. The central theme of this proposal is that muscle-specific phenotypes arise from specific abnormalities in nuclear envelope function, ranging from impaired structural function to abnormal transcriptional regulation, resulting in impaired adaptive and protective pathways. My specific aims are to: 1. Characterize the specific effects of mutations linked to Emery-Dreifuss muscular dystrophy on nuclear stability and cellular sensitivity to mechanical strain. Using recently established techniques, I will test the hypothesis that skin fibroblasts from Emery-Dreifuss muscular dystrophy patients have specifically impaired nuclear stability and abnormal regulation of mechanosensitive genes, resulting in decreased cell viability under strain. Cells from familial partial lipodystrophy patients and healthy control subjects will serve as controls for non-specific defects and normal nuclear envelope function, respectively. 2. Identify the muscle-specific effects of these mutations on nuclear mechanics and gene regulation. To test the hypothesis that tissue-specific defects in nuclear stability and mechanotransduction contribute to the muscular phenotype in Emery-Dreifuss muscular dystrophy, I will compare nuclear mechanics, strain- induced gene regulation, and cell viability under strain in muscle cells derived from mouse models of Emery- Dreifuss muscular dystrophy with fibroblasts from the same animals and with cells from wild-type littermates. Studying the specific cellular defects of these mutations will help to improve our understanding of normal and tissue-specific functions of the nuclear envelope and lead to new insights into the molecular mechanisms responsible for Emery-Dreifuss muscular dystrophy and other laminopathies such as limb-girdle muscular dystrophy, potentially providing new targets for the treatment of these diseases.

描述（由申请人提供）：核是真核细胞的区别特征，并通过核包膜与周围的细胞质分离。核包膜蛋白的突变层层粘连蛋白A/C和Emerin会引起emery-dreifuss肌肉营养不良，肢体束缚肌营养不良，家族性部分脂肪营养不良以及多种其他疾病，称为层状层。潜在的疾病机制尚不清楚，部分原因是核包膜蛋白的功能未完全定义。我的长期目标是了解分子机制，通过这些机制，这些无处不在表达的蛋白质中的突变会导致这种组织特异性表型。该提案的中心主题是肌肉特异性表型是由核包膜功能的特定异常引起的，从结构功能受损到异常转录调节，导致适应性和保护性途径受损。我的具体目的是：1。表征了与默里 - 二曲肌肉营养不良有关的突变对核稳定性和对机械应变的细胞敏感性的特定作用。使用最近建立的技术，我将检验以下假设：来自emery-dreifuss肌肉营养不良患者的皮肤成纤维细胞明确损害了机械敏感基因的核稳定性和异常调节，从而导致细胞生存能力降低。家族性部分脂肪营养不良患者和健康对照组受试者的细胞将分别作为非特异性缺陷和正常核包膜功能的对照。 2。确定这些突变对核力学和基因调节的肌肉特异性作用。为了检验核稳定性和机械传导中组织特异性缺陷的假说有助于默克 - 二曲肌肉营养不良中的肌肉表型，我将比较核力学，基因调节的核力学，细胞调节，以及细胞在菌株中的细胞生存能力以及来自来自肌肉的肌肉细胞的菌株，以及来自肌分泌的肌肉模型，野生式同窝仔。研究这些突变的特异性细胞缺陷将有助于提高我们对核包膜正常和组织特异性功能的理解，并导致对负责默里 - 二氧化肌营养不良和其他层状薄膜病变的分子机制的新见解，例如为肌肉肌营养不良症，潜在地提供这些新靶标，以提供这些新靶标的新靶标，以提供这些新靶标的这些疾病。