Novel Regulatory Pathway in Prevention of Atherosclerosis

预防动脉粥样硬化的新调控途径

• 批准号: 8666531
• 负责人: SHUNLIN REN
• 金额: --
• 依托单位: VA VETERANS ADMINISTRATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8666531
• 关键词: 25-hydroxycholesterol; Animal Model; Arterial Fatty Streak; Atherosclerosis; Binding Proteins; Blood; Cell Nucleus; Cholesterol; Cholesterol Homeostasis; Clinical; Data; Development; Diet; Disease; Enzymes; Event; Failure; Fatty acid glycerol esters; Foam Cells; Functional disorder; Gene Expression; Glycols; Goals; Health; Homologous Gene; In Vitro; Inflammation; Inflammatory Response; Inorganic Sulfates; Knowledge; Lead; Lipid-Laden Macrophage; Lipids; Liver; Metabolic; Metabolic Pathway; Modeling; Molecular; Nonesterified Fatty Acids; Nuclear; Nuclear Receptors; Pathogenesis; Play; Population; Positioning Attribute; Prevention; Receptor Signaling; Regulation; Regulatory Pathway; Reporting; Research; Response Elements; Role; Signal Transduction; Sterols; Testing; Transgenic Mice; Unspecified or Sulfate Ion Sulfates; Veterans; base; cell type; disability; in vivo; lipid metabolism; macrophage; mortality; mouse model; new therapeutic target; novel; novel therapeutics; overexpression; prevent; public health relevance; receptor; research study; sulfation; sulfotransferase

DESCRIPTION (provided by applicant): Atherosclerotic diseases are the leading cause of mortality in Veteran population. Macrophages are the most prominent cell type in atherosclerotic lesions. The lipid-laden macrophages (foam cells) formation and subsequent inflammation in the arterial wall are the major pathogenesis for development of the diseases. Nuclear receptors have been reported to play a critical role in the lipid metabolism and inflammatory response. However, the regulation of their activity is unclear. It has been shown that there are major perturbations in cholesterol metabolism. The potential mechanisms by which such perturbations may lead to atherosclerosis via nuclear receptor signaling remain unclear. This knowledge gap in the field is a major barrier towards understanding the role of cholesterol metabolites in the pathogenesis of atherosclerosis and leveraging this information to develop novel therapies for atherosclerosis. We hypothesize that decreased SULT2B1b activity with consequent decreases in its metabolic product 25HC3S promotes atherosclerosis by (1) dysinhibition of the pro- lipogenic transcriptional factor, sterol response element binding protein-1c (SREBP-1c), due to failure to inactivate oxysterol signaling; and (2) disability of suppressing of inflammatory responses by decreasing IkB levels. These dysfunctions are caused by failure to regulate nuclear liver receptor homologue-1 (LRH-1). We will test the hypothesis by the following specific aims: 1). To explore that decreased SULT2B1b activity with consequent decreases in its metabolic product 25HC3S promotes atherosclerosis in vitro in free fatty acid-induced and in vivo high fat diet-induced atherosclerotc models. 2). To test potential of overexpression of SULT2B1b and administration 25HC3S to prevent/reverse lipid accumulation in blood and aortic wall in animal models. 3) To elucidate the molecular mechanism by which 25HC3S regulates LRH-1 activity: its role in lipid metabolism and inflammatory responses. These will provide a sufficient scientific background for development of new therapeutic strategies. The successful completion of the proposed studies will positively impact the field by: 1) providing a novel mechanism for the development of atherosclerosis, 2) identifying novel therapeutic targets for the treatment of atherosclerosis, and (3) opening new avenues of research focusing on the role of disordered cholesterol metabolism in the genesis and progression of atherosclerotic diseases.

描述(由申请人提供)： 动脉粥样硬化性疾病是导致退伍军人死亡的主要原因。巨噬细胞是动脉粥样硬化病变中最主要的细胞类型。动脉壁富含脂质的巨噬细胞(泡沫细胞)的形成和随后的炎症是疾病发展的主要发病机制。核受体已被报道在脂质代谢和炎症反应中发挥关键作用。然而，对他们活动的监管尚不清楚。已有研究表明，胆固醇代谢存在较大的紊乱。这种干扰可能通过核受体信号导致动脉粥样硬化的潜在机制尚不清楚。这一领域的知识差距是理解胆固醇代谢物在动脉粥样硬化发病机制中的作用并利用这些信息开发治疗动脉粥样硬化的新疗法的主要障碍。我们假设，SULT2B1b活性降低，其代谢产物25HC3S通过以下方式促进动脉粥样硬化：(1)由于未能激活氧固醇信号，导致促脂肪生成转录因子-类固醇反应元件结合蛋白-1c(SREBP-1c)的失调；以及(2)通过降低IKB水平来抑制炎症反应。这些功能障碍是由于未能调节核肝受体同源1(LRH-1)而引起的。我们将通过以下具体目标来检验这一假设：1)。探讨SULT2B1b活性降低及其代谢产物25HC3S在体外游离脂肪酸诱导和体内高脂饮食诱导的动脉粥样硬化模型中促进动脉粥样硬化。2)。目的：检测SULT2B1b基因过表达和25HC3S给药对动物模型血和主动脉壁脂类蓄积的影响。3)阐明25HC3S调节LRH-1活性的分子机制：其在脂质代谢和炎症反应中的作用。这些将为开发新的治疗策略提供充分的科学背景。拟议研究的成功完成将通过以下方式对该领域产生积极影响：1)为动脉粥样硬化的发展提供新的机制；2)确定治疗动脉粥样硬化的新靶点；以及 (3)开辟新的研究途径，重点研究胆固醇代谢紊乱在动脉粥样硬化性疾病的发生和发展中的作用。