Regulation of Macrophage Reverse Cholesterol Transport by BRCA1

BRCA1 对巨噬细胞反向胆固醇转运的调节

基本信息

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
项目类别：
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

项目摘要

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将巨噬细胞募集到血管壁的潜在上皮层以及不受控制的氧化胆固醇的摄取。通过巨噬细胞和相关的炎症反应持续积累氧化胆固醇会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累的过程已被视为一种潜在的对心血管疾病的新型治疗方法，但是除了可注射的载脂蛋白A1的可注射形式以外。尚未在诊所验证巨噬细胞反向胆固醇转运（RCT）的药物在人类中使用。肝X受体LXR和LXR已被确定为胆固醇稳态的重要调节剂。合成LXR激动剂的治疗至少部分通过刺激巨噬细胞RCT来降低心血管疾病动物模型的动脉粥样硬化。 LXR激动剂增强巨噬细胞RCT的能力激发了对这些药物的治疗潜力的极大兴趣。然而，LXR激动剂诱导肝脂肪生成的倾向减慢了这些化合物向诊所的发展。我们认为，鉴定控制LXR活性的蛋白质可能揭示了调节巨噬细胞RCT和心血管疾病的新方法。在寻找这些因素时，我们已经确定乳腺癌和卵巢癌易感性1基因产物（BRCA1）是一种有选择地控制LXR活性的蛋白质。先前的研究表明，BRCA1及其异二聚体伴侣BRCA1环相关结构域1（BARD1）作为控制多个核受体的半衰期的E3泛素连接酶的功能。我们的初步数据表明，bard1/brca1的耗竭增加了LXR的半衰期，并减少其转录活性，而几乎没有或没有对LXR的影响。重要的是，是LXR亚型在调节巨噬细胞RCT中起主要作用。 BARD1/BRCA1对DNA修复，基因组稳定性和肿瘤发生的贡献已经得到很好的研究。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理中发挥了新的意外作用。我们将使用遗传方法在巨噬细胞中耗尽BARD1/BRCA1以及基因组广泛的分析，以确定Bard1/Brca1对控制巨噬细胞RCT的控制的贡献，并定义BRCA1在巨噬细胞中控制的遗传网络。我们认为，这些研究将通过确定BARD1/BRCA1的潜在新作用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功能的理解的范式转移，从而可以促进RCT途径的治疗靶向。