Regulation of Macrophage Reverse Cholesterol Transport by BRCA1

BRCA1 对巨噬细胞反向胆固醇转运的调节

• 批准号: 8278812
• 负责人: Ira G Schulman
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-12 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278812
• 关键词: Acute; Adult; Agonist; American Heart Association; Animal Model; Apolipoprotein A-I; Atherosclerosis; BRCA1 Protein; BRCA1 gene; Biology; Blood Vessels; Cardiovascular Diseases; Cells; Cholesterol; Cholesterol Homeostasis; Clinic; DNA Repair; Data; Development; Epithelial; Estrogen Receptors; Event; Foam Cells; Funding Mechanisms; Genetic; Genome Stability; Goals; Half-Life; Hepatic; Human; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injectable; Life; Liver; Malignant neoplasm of ovary; Microarray Analysis; Mus; Nuclear Hormone Receptors; Nuclear Receptors; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Play; Predisposition; Process; Proteins; Regulation; Risk; Role; Signal Transduction; Small Interfering RNA; Therapeutic; Tissues; Transcriptional Regulation; United States; Western World; genome-wide; high risk; in vivo; innovation; interest; lipid biosynthesis; macrophage; malignant breast neoplasm; member; novel; novel strategies; protein function; receptor; research study; response; reverse cholesterol transport; statistics; therapeutic target; therapy development; transcription factor; tumorigenesis; ubiquitin-protein ligase; uptake

DESCRIPTION (provided by applicant): A critical event in the development of atherosclerosis is the recruitment of macrophages to the underlying epithelial layer of blood vessel walls and the uncontrolled uptake of oxidized cholesterol. Continued accumulation of oxidized cholesterol by macrophages and an associated inflammatory response leads to foam cell formation and the initiation of atherosclerosis. Reversing the process of macrophage cholesterol accumulation has been held out as a potential novel treatment for cardiovascular disease, however other than injectable forms of apolipoprotein A1; no drugs that enhance macrophage reverse cholesterol transport (RCT) have been validated in the clinic for use in humans. The liver X receptors LXR and LXR have been identified as important regulators of cholesterol homeostasis. Treatment with synthetic LXR agonists reduces atherosclerosis in animal models of cardiovascular disease at least in part by stimulating macrophage RCT. The ability of LXR agonists to enhance macrophage RCT has stimulated great interest in the therapeutic potential of these agents. Nevertheless, the propensity of LXR agonists to induce hepatic lipogenesis has slowed the progression of these compounds to the clinic. We reasoned that identifying proteins that control LXR activity may reveal new approaches for the regulation of macrophage RCT and cardiovascular disease. In a search for such factors we have identified the Breast and Ovarian Cancer Susceptibility 1 gene product (BRCA1) as a protein that selectively controls LXR activity. Previous studies have demonstrated that BRCA1 and its heterodimeric partner BRCA1 ring associated domain 1 (BARD1) function as an E3 ubiquitin ligase that controls the half-life of several nuclear receptors. Our preliminary data indicates that depletion of BARD1/BRCA1 increases the half-life of LXR and decreases its transcriptional activity while having little or no effect on LXR. Importantly, it is the LXR subtype which plays the dominant role in regulating macrophage RCT. The contributions of BARD1/BRCA1 to DNA repair, genome stability and oncogenesis have been well studied. Our preliminary studies, however, suggest a new and unexpected role for BARD1/BRCA1 in the pathogenesis of cardiovascular disease and macrophage biology. We will use genetic approaches to deplete BARD1/BRCA1 in macrophages along with genome wide profiling to determine the contribution of BARD1/BRCA1 to the control of macrophage RCT and to define the genetic networks controlled by BRCA1 in macrophages. We believe that these studies will facilitate a paradigm shift in our understanding of BARD1/BRCA1 function by identifying potential new roles for BARD1/BRCA1 in the control of macrophage function that may facilitate the therapeutic targeting of the RCT pathway. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is the leading killer of adults in the Western world and statistics from the American Heart Association indicate that more than 50% of adults living in the United States have cholesterol levels that put them at risk for atherosclerosis. Our preliminary results suggest that the Breast and Ovarian Cancer Susceptibility 1 gene product (BRCA1) is an important regulator of cholesterol homeostasis and the experimental approaches described in this application will define the role of BRCA1 in regulating cholesterol levels and inflammation. The results of these studies should provide innovative strategies for the development of therapies for the treatment of cardiovascular disease.

描述（由申请人提供）：动脉粥样硬化发展中的一个关键事件是巨噬细胞募集到血管壁的下层上皮层以及氧化胆固醇的不受控制的摄取。巨噬细胞持续积累氧化胆固醇和相关的炎症反应，导致泡沫细胞形成并引发动脉粥样硬化。逆转巨噬细胞胆固醇积累过程已被认为是治疗心血管疾病的一种潜在新疗法，但除了注射形式的载脂蛋白 A1 之外；目前还没有任何增强巨噬细胞反向胆固醇转运 (RCT) 的药物经过临床验证可用于人类。肝脏 X 受体 LXR 和 LXR 已被确定为胆固醇稳态的重要调节因子。合成 LXR 激动剂治疗至少部分通过刺激巨噬细胞 RCT 来减少心血管疾病动物模型中的动脉粥样硬化。 LXR 激动剂增强巨噬细胞 RCT 的能力引起了人们对这些药物治疗潜力的极大兴趣。然而，LXR 激动剂诱导肝脏脂肪生成的倾向减缓了这些化合物进入临床的进程。我们推断，识别控制 LXR 活性的蛋白质可能会揭示调节巨噬细胞 RCT 和心血管疾病的新方法。在寻找这些因素的过程中，我们发现乳腺癌和卵巢癌易感性 1 基因产物 (BRCA1) 是一种选择性控制 LXR 活性的蛋白质。先前的研究表明，BRCA1 及其异二聚体伙伴 BRCA1 环相关结构域 1 (BARD1) 作为 E3 泛素连接酶发挥作用，控制多种核受体的半衰期。我们的初步数据表明，BARD1/BRCA1 的耗尽会增加 LXR 的半衰期并降低其转录活性，同时几乎没有或没有 对LXR的影响。重要的是，LXR亚型在调节巨噬细胞RCT中起主导作用。 BARD1/BRCA1 对 DNA 修复、基因组稳定性和肿瘤发生的贡献已得到充分研究。然而，我们的初步研究表明 BARD1/BRCA1 在心血管疾病和巨噬细胞生物学的发病机制中具有新的、意想不到的作用。我们将使用遗传方法来消除巨噬细胞中的 BARD1/BRCA1 以及全基因组分析，以确定 BARD1/BRCA1 对巨噬细胞 RCT 控制的贡献，并定义巨噬细胞中 BRCA1 控制的遗传网络。我们相信，这些研究将通过确定 BARD1/BRCA1 在控制巨噬细胞功能中的潜在新作用，从而促进我们对 BARD1/BRCA1 功能的理解发生范式转变，从而促进 RCT 途径的治疗靶向。 公共卫生相关性：心血管疾病是西方世界成年人的头号杀手，美国心脏协会的统计数据表明，超过 50% 的美国成年人的胆固醇水平使他们面临动脉粥样硬化的风险。我们的初步结果表明，乳腺癌和卵巢癌易感性 1 基因产物 (BRCA1) 是胆固醇稳态的重要调节剂，本申请中描述的实验方法将确定 BRCA1 在调节胆固醇水平和炎症中的作用。这些研究的结果应该为开发治疗心血管疾病的疗法提供创新策略。