Novel Regulatory Pathway in Prevention of Atherosclerosis

描述（由申请人提供）： 动脉粥样硬化疾病是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突出的细胞类型。载脂巨噬细胞（泡沫细胞）的形成和随后的动脉壁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起关键作用。 然而，对其活动的监管尚不清楚。已经表明，胆固醇代谢存在重大扰动。这种扰动可能通过核受体信号传导导致动脉粥样硬化的潜在机制尚不清楚。 该领域的知识差距是理解胆固醇代谢产物在动脉粥样硬化发病机制中的作用以及利用这些信息开发动脉粥样硬化新疗法的主要障碍。 我们推测，SULT 2B 1b活性降低及其代谢产物25 HC 3S随之减少通过以下方式促进动脉粥样硬化：（1）由于氧化甾醇信号传导失败，促脂肪生成转录因子甾醇反应元件结合蛋白-1c（SREBP-1c）的功能障碍;（2）通过降低IkB水平抑制炎症反应的能力丧失。这些功能障碍是由于未能调节核肝受体同源物-1（LRH-1）引起的。 我们将通过以下具体目标来检验假设：1）。在游离脂肪酸诱导的体外和体内高脂饮食诱导的动脉粥样硬化模型中，探索SULT 2B 1b活性降低及其代谢产物25 HC 3S随之降低促进动脉粥样硬化。2）。在动物模型中测试SULT 2B 1b过表达和施用25 HC 3S预防/逆转血液和主动脉壁中脂质蓄积的潜力。3)阐明25 HC 3S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治疗靶点， (3)开辟了新的研究途径，重点是胆固醇代谢紊乱在动脉粥样硬化疾病的发生和发展中的作用。

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.