BRCA1 is necessary for optimal skeletal muscle function

 描述（由申请人提供）：BRCA 1基因在癌症易感性中的作用是众所周知的，部分原因是其对错义突变的高度易感性。该基因编码一种调节细胞内多种功能的大蛋白质;然而，这些功能中的大多数仅在乳腺组织中描述。通常被低估的是BRCA 1表达模式超出女性生殖组织的事实。例如，我们发现BRCA 1在骨骼肌中表达，但此时BRCA 1在骨骼肌中没有明确的作用。在这里，我们的目标是使用一个综合的方法来描绘机制BRCA 1调节骨骼肌。我们的初步数据表明，通过使用诱导型基因消融方法，骨骼肌中BRCA 1功能的丧失导致肌无力、脊柱后凸、运动不耐受和线粒体功能降低。第一个具体目标将寻求确定BRCA 1表达是否对骨骼肌功能至关重要。第二个具体目标将寻求确定BRCA 1表达是否是骨骼肌线粒体功能所必需的。第三个具体目标将寻求确定BRCA 1基因中已知的错义突变是否有助于骨骼肌功能降低。在这个建议中，我们将使用最先进的生理和分子 方法作为一种手段来阐明生理机制BRCA 1调节骨骼肌。由于BRCA 1存在大量的遗传变异，因此了解BRCA 1在骨骼肌中的调节机制有可能有助于预防肌肉减少症，身体残疾等疾病。

 DESCRIPTION (provided by applicant): The BRCA1 gene is well known for its role in cancer susceptibility in part due to its high susceptibility to missense mutations. The gene encodes a large protein that regulates multiple functions within the cell; however the majority of these functions have only been described in mammary tissue. What is generally under-appreciated is the fact that BRCA1 expression patterns extend beyond female reproductive tissue. For example, we have found that BRCA1 is expressed in skeletal muscle, but at this time BRCA1 has no defined role in skeletal muscle. Here our goal is to use an integrative approach to delineate the mechanisms BRCA1 regulate in skeletal muscle. Our preliminary data demonstrate that loss of BRCA1 function in skeletal muscle through use of an inducible genetic ablation approach results in muscle weakness, kyphosis, exercise intolerance, and reduced mitochondrial function. The first specific aim will seek to determine if BRCA1 expression is critical for skeletal muscle function. The second specific aim will seek to determine if BRCA1 expression is necessary for mitochondrial function in skeletal muscle. The third specific aim will seek to determine if known missense mutations in the BRCA1 gene contribute to reduced skeletal muscle function. In this proposal we will use state-of-the-art physiological and molecular approaches as a means to elucidate the physiological mechanisms BRCA1 regulates in skeletal muscle. Since BRCA1 presents with a significant amount of genetic variation, understanding the mechanisms that BRCA1 regulates in skeletal muscle have the potential to aid in the prevention of conditions such as sarcopenia, physical disability, etc.