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: 8440745
• 负责人: Ira G Schulman
• 金额: $ 21.99万
• 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 2014-05-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8440745
• 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.

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重新聚集到血管壁的底层上皮层，并不受控制地摄取氧化胆固醇。巨噬细胞氧化胆固醇的持续积累和相关的炎症反应导致泡沫细胞的形成和动脉粥样硬化的启动。逆转巨噬细胞胆固醇积聚的过程一直被认为是治疗心血管疾病的潜在新疗法，然而，除了注射形式的载脂蛋白A1外，还没有增强巨噬细胞胆固醇反向转运(RCT)的药物在临床上得到验证。肝X受体LXR和LXR被认为是胆固醇稳态的重要调节因子。合成LXR激动剂的治疗减少了心血管疾病动物模型的动脉粥样硬化，至少部分是通过刺激巨噬细胞RCT。LXR激动剂增强巨噬细胞RCT的能力激发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展。我们认为，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。以往的研究表明，BRCA1及其异二聚体BRCA1环相关结构域1(BARD1)是一种E3泛素连接酶，控制着多种核受体的半衰期。我们的初步数据表明，BARD1/BRCA1的缺失增加了LXR的半衰期，降低了其转录活性，但几乎没有或几乎没有 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在DNA修复、基因组稳定性和肿瘤发生中的作用已经得到了很好的研究。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扮演了一个新的和意想不到的角色。我们将使用基因方法去除巨噬细胞中的BARD1/BRCA1，并结合全基因组图谱来确定BARD1/BRCA1在巨噬细胞RCT调控中的作用，并确定由BRCA1控制的巨噬细胞中的遗传网络。我们相信，这些研究将通过确定BARD1/BRCA1在巨噬细胞功能控制中的潜在新角色，促进RCT通路的治疗靶向，从而促进我们对BARD1/BRCA1功能的理解的范式转变。