The role of BRCA1 in regulation of lipid metabolism in skeletal muscle

BRCA1在骨骼肌脂质代谢调节中的作用

• 批准号: 8112903
• 负责人: ESPEN E SPANGENBURG
• 金额: $ 20.1万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-20 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8112903
• 关键词: Ablation; Acetyl-CoA Carboxylase; Acute; Address; Animals; BRCA1 gene; Binding; Central obesity; Clinical; Complementary DNA; Coupled; Data; Development; Electroporation; Endocrine disruption; Estrogen Therapy; Estrogens; Exercise; Exhibits; Fatty acid glycerol esters; Female; Genetic; Glucose; Goals; Health; In Vitro; Intervention; Knowledge; Lead; Life; Lipids; Mammary Gland Parenchyma; Measures; Mediating; Menopause; Metabolic; Metabolic Diseases; Metabolic syndrome; Metformin; Mitochondria; Modality; Modeling; Mus; Muscle; Mutation; Obesity; Operative Surgical Procedures; Ovarian hormone; Ovariectomy; Ovary; Palmitates; Pattern; Phenotype; Phosphorylation; Physiological; Play; Postmenopause; Publishing; Regulation; Respiration; Risk; Role; Signal Transduction; Skeletal Muscle; Symptoms; Time; Visceral; Woman; Women' s Health; design; early onset; gain of function; in vivo; lipid metabolism; loss of function; malignant breast neoplasm; meetings; mouse model; novel; oxidized lipid; response

DESCRIPTION (provided by applicant): Menopause begins in the fifth decade of life and results in decreased circulating estrogens which coincides with increases in visceral fat mass placing women at elevated risk for the developing the metabolic syndrome. With the release of the Women's Health Initiative doctors have to reconsider current options for treating postmenopausal women. It is increasingly important to understand the physiological consequences of the loss of ovarian hormones (i.e. estrogens) on women's health so new interventions can be developed. Our data indicate that ovariectomized animals (OVX) exhibit symptoms of the metabolic syndrome, including increased visceral fat, impaired glucose dynamics and high circulating levels of lipid. We believe these changes in the OVX mice are due to a reduced ability of the skeletal muscle to effectively oxidize lipid, which we hypothesize is mediated in part by the gene breast cancer early onset 1 (BRCA1). This study will delineate the role of BRCA1 in regulating lipid entry into the mitochondria of skeletal muscle and attempt to determine if decreases in BRCA1 expression contribute to increased abdominal obesity in the OVX model. PUBLIC HEALTH RELEVANCE: Large decreases in circulating estrogen concentration either via menopause or surgical ovariectomy results in increased visceral adiposity. Since estrogen therapy is not considered a viable option, this proposal will seek to understand how skeletal muscle changes when exposed low levels of estrogens over an extended period of time. Here, we have designed an in-depth exploratory study that will address the dysregulation of cellular mechanisms that regulate lipid utilization in post-menopausal women.

描述（由申请人提供）：更年期从五岁开始，导致循环雌激素减少，同时内脏脂肪量增加，使女性患代谢综合征的风险升高。随着妇女健康倡议的发布，医生必须重新考虑当前治疗绝经后妇女的选择。了解卵巢激素（即雌激素）丧失对女性健康的生理后果变得越来越重要，以便开发新的干预措施。我们的数据表明，卵巢切除动物（OVX）表现出代谢综合征的症状，包括内脏脂肪增加、葡萄糖动力学受损和脂质循环水平升高。我们相信 OVX 小鼠的这些变化是由于骨骼肌有效氧化脂质的能力降低所致，我们假设这种变化部分是由乳腺癌早发基因 1 (BRCA1) 介导的。这项研究将描述 BRCA1 在调节脂质进入骨骼肌线粒体中的作用，并试图确定 BRCA1 表达的减少是否会导致 OVX 模型中腹部肥胖的增加。 公共卫生相关性：通过绝经或手术卵巢切除术导致循环雌激素浓度大幅下降，导致内脏肥胖增加。由于雌激素疗法不被认为是可行的选择，因此该提案将寻求了解在长时间暴露于低水平雌激素时骨骼肌如何变化。在这里，我们设计了一项深入的探索性研究，将解决调节绝经后女性脂质利用的细胞机制失调问题。