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. ? ? ?
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