Anti-inflammatory, cholesterol export, and cardioprotective functions of ABCA1

ABCA1 的抗炎、胆固醇输出和心脏保护功能

基本信息

批准号：
7759216
负责人：
RENEE C LEBOEUF
金额：
$ 41.5万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7759216
关键词：
ATP-Binding Cassette Transporters Amino Acid Motifs Animals Anti-Inflammatory Agents Anti-inflammatory Apolipoprotein A-I Apolipoproteins Arteries Atherosclerosis Biochemical Cardiovascular Diseases Cell Culture Techniques Cell Membrane Proteins Cell physiology Cells Cholesterol Development Engineering Excision Goals Heart Heart Diseases High Density Lipoproteins Hormonal Impairment In Vitro Inflammation Inflammatory Inflammatory Response Janus kinase 2 Link Lipids Mass Spectrum Analysis Metabolism Molecular Morbidity - disease rate Mus Mutagenesis Pathway interactions Peptides Phospholipids Plasma Process Production Property Protein Export Pathway Protein Tyrosine Kinase Proteins Receptor Signaling Research Role STAT3 gene Signal Pathway Site Techniques Testing Therapeutic Therapeutic Effect Therapeutic Intervention Transplantation Western World Wild Type Mouse atherogenesis cardiovascular risk factor clinically relevant cytokine density in vivo insight macrophage mimetics mortality mouse model novel strategies prevent public health relevance receptor reverse cholesterol transport therapeutic target transcription factor

项目摘要

DESCRIPTION (provided by applicant): Atherosclerotic cardiovascular disease (CVD) is the most common cause of mortality and morbidity in the Western world. Cholesterol accumulation in arterial macrophages and inflammation of the artery wall both contribute to development of CVD. There is an inverse relationship between plasma high-density (HDL) levels and cardiovascular risk, implying that factors associated with HDL metabolism are cardioprotective. HDL protects against CVD by several mechanisms that remove cholesterol from arterial cells and suppress inflammation. A major cardioprotective factor associated with HDL metabolism is ATP-binding cassette transporter A1 (ABCA1), a cell membrane protein that exports cholesterol and phospholipids from cells to lipid-depleted HDL apolipoproteins, such as apoA-I. We found that ABCA1 also functions as an anti-inflammatory signaling receptor through activation of a JAK2/STAT3 pathway, which is independent of cholesterol export activity. Thus, macrophage ABCA1 provides a direct biochemical link between the cardioprotective effects of reverse cholesterol transport and suppressed inflammation. These observations indicate that ABCA1 is an attractive therapeutic target for treating the two major underlying mechanisms that cause CVD. The goal of this project is to determine the cellular processes involved in the cholesterol export and anti-inflammatory activities of ABCA1 and to assess their cardioprotective roles in vivo. We propose to use mutagenesis, biochemical, and mass spectrometric techniques to evaluate the effects of apolipoprotein-ABCA1 interactions on cholesterol export and inflammatory cytokine production and to characterize cellular mechanisms involved. We also propose to use atherosclerosis-susceptible mouse models to determine how these anti-inflammatory and cholesterol export functions of ABCA1 contribute to atherosclerosis in whole animals. This information will define possible sites of impairment of these pathways that may be clinically relevant and uncover potential targets for therapeutic interventions for preventing CVD. PUBLIC HEALTH RELEVANCE: HDL protects against heart disease by removing artery-blocking cholesterol from arterial cells and inhibiting inflammation. A cell protein called ABCA1 can perform both of these heart-protecting functions. This research will investigate the cell pathways involved in the cholesterol removal and anti-inflammatory actions of ABCA1 and determine if these pathways protect against heart disease in animals.

描述（由申请人提供）：动脉粥样硬化心血管疾病（CVD）是西方世界中死亡率和发病率的最常见原因。动脉巨噬细胞中的胆固醇积累和动脉壁的炎症都有助于CVD的发展。血浆高密度（HDL）水平与心血管风险之间存在反比关系，这意味着与HDL代谢相关的因素是心脏保护性的。 HDL通过几种从动脉细胞中去除胆固醇并抑制炎症的机制来预防CVD。与HDL代谢相关的主要心脏保护因子是ATP结合盒转运蛋白A1（ABCA1），这是一种细胞膜蛋白，将胆固醇和磷脂从细胞中导出到脂质耗尽的HDL载脂蛋白，例如Apoa-i。我们发现，ABCA1还通过激活JAK2/STAT3途径的激活作为抗炎信号受体，该途径与胆固醇的出口活性无关。因此，巨噬细胞ABCA1在反向胆固醇转运的心脏保护作用与抑制炎症之间提供了直接的生化联系。这些观察结果表明，ABCA1是治疗引起CVD的两种主要潜在机制的有吸引力的治疗靶标。该项目的目的是确定ABCA1胆固醇出口和抗炎活性所涉及的细胞过程，并评估其在体内的心脏保护作用。我们建议使用诱变，生化和质谱技术来评估载脂蛋白-ABCA1相互作用对胆固醇输出和炎性细胞因子产生的影响，并表征涉及的细胞机制。我们还建议使用动脉粥样硬化敏感的小鼠模型来确定ABCA1的这些抗炎和胆固醇输出功能如何有助于整个动物的动脉粥样硬化。该信息将定义这些途径受损的可能位点，这些途径可能在临床上相关且揭示了预防CVD的治疗干预措施的潜在靶标。公共卫生相关性：HDL通过将动脉阻塞胆固醇从动脉细胞中去除并抑制炎症来预防心脏病。称为ABCA1的细胞蛋白可以执行这两种心脏保护功能。这项研究将研究ABCA1的胆固醇去除和抗炎作用所涉及的细胞途径，并确定这些途径是否可以预防动物心脏病。