BRCA1 is necessary for optimal skeletal muscle function

BRCA1 对于最佳骨骼肌功能是必需的

基本信息

批准号：
8886653
负责人：
ESPEN E SPANGENBURG
金额：
$ 33.61万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8886653
关键词：
Ablation Affect Age Animals Antioxidants BRCA1 Mutation BRCA1 Protein BRCA1 gene BRCT Domain Biology Breast Cancer Cell Cancer-Predisposing Gene Cells Chronic Coupling DNA Sequence Alteration Data Development Diet Disease Electroporation Erythroid Exercise Exposure to Fatigue Fatty acid glycerol esters Female Functional disorder Genes Genetic Genetic Variation Genomics Genotype Goals Health Human In Situ Individual Knockout Mice Kyphosis deformity of spine Lead Maintenance Malignant Neoplasms Malignant neoplasm of ovary Mammary gland Measures Missense Mutation Mitochondria Mitochondrial DNA Molecular Mus Muscle Muscle Cells Muscle Fibers Muscle Weakness Muscle function Muscular Dystrophies Mutate Mutation Neuromuscular Junction Nuclear Output Oxidation-Reduction Patients Pattern Physical Function Physically Handicapped Physiological Positioning Attribute Predisposition Prevention Production Proteins Reactive Oxygen Species Regulation Risk Role Skeletal Muscle System Time Tissues Translating Triceps Brachii Muscle Ubiquitination Variant Wild Type Mouse aged base cancer risk genetic variant mRNA Expression male malignant breast neoplasm mitochondrial DNA mutation novel public health relevance repaired reproductive research study sarcopenia sex tool translational study

项目摘要

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.

描述（由申请人提供）：BRCA1 基因因其在癌症易感性中的作用而闻名，部分原因是其对错义突变的高度敏感。仅在乳腺组织中进行了描述，但人们普遍低估了 BRCA1 表达模式超出了女性生殖组织的事实，例如，我们发现 BRCA1 在骨骼中表达。肌肉，但目前 BRCA1 在骨骼肌中没有明确的作用，我们的目标是使用综合方法来描述 BRCA1 在骨骼肌中的调节机制。我们的初步数据表明，通过使用 BRCA1 在骨骼肌中的功能会丧失。诱导性基因消融方法会导致肌肉无力、脊柱后凸、运动不耐受和线粒体功能降低。第一个具体目标是确定 BRCA1 表达是否对这一过程至关重要。第二个具体目标是确定 BRCA1 表达是否是骨骼肌线粒体功能所必需的；第三个具体目标是确定 BRCA1 基因中已知的错义突变是否会导致骨骼肌功能降低。我们将使用最先进的生理和分子技术作为阐明 BRCA1 在骨骼肌中调节的生理机制的一种方法，由于 BRCA1 存在大量遗传变异，因此了解 BRCA1 在骨骼肌中的调节机制有可能有助于预防肌肉减少症、身体疾病等疾病。残疾等