LXR as a novel therapeutic target in diabetic retinopathy

 描述(由申请人提供)：支持脂质在糖尿病视网膜病变相关血管损害中作用的临床研究，包括DCCT/EDIC、ACCORD、蓝山眼研究和WESDR研究，表明视网膜脂质水平可能比循环脂肪水平更关键。DR不仅是内皮损伤的结果，也是血管修复不足的结果。血脂异常通过有害地影响循环血管生成细胞(CACs)对血管修复产生不利影响，循环血管生成细胞(CACs)是一种修复性的骨髓来源(BMD)细胞群。血脂异常还促进视网膜的促炎环境，并激活骨密度炎症细胞，特别是单核细胞。因此，全身性和视网膜脂质异常同时减少了血管修复，并通过增加炎症促进了血管损伤。在这一应用中，我们通过检查一个新的轴来深入了解DR的发病机制，该轴统一了关键的脂质调节因子SIRT1和肝脏X受体(LXRa/LXR？)。SIRT1是NAD依赖的蛋白去乙酰基酶中sirtuin家族的成员，在DR中表达降低。SIRT1对新陈代谢和炎症的有利作用被证明是通过激活LXR来介导的。此前，我们在啮齿动物模型中证明了肝X受体(LXRa/LXR？)的药理激活可以预防DR。在这项提议中，我们检验了糖尿病引起的SIRT1-LXR轴的破坏会导致脂代谢异常和炎症的假设。刺激这一轴的策略将导致激活细胞和组织中胆固醇的清除，使胆固醇稳态正常化，并抑制靶组织(视网膜)和细胞(CACs和单核/巨噬细胞)中的炎症基因iNOS、IL-1ç、ICAM-1和CCL2。我们提出以下具体目标：目的1：确定SIRT1-LXR轴的激活是否通过降低视网膜中iNOS、IL-1？、ICAM-1和CCL2炎症基因的表达而逆转糖尿病所致的视网膜损伤。目的：研究SIRT1-LXR轴的激活是否通过纠正CAC膜流动性接近正常而逆转糖尿病所致的CACs功能障碍，改善其修复功能，从而促进其从骨髓(BM)向视网膜损伤区域的迁移，促进血管修复。目的：确定SIRT1-LXR轴的激活是否调节先天免疫反应，从而纠正糖尿病引起的单核细胞增多症，并调节局部和全身巨噬细胞/单核细胞极化。

 DESCRIPTION (provided by applicant): Clinical studies supporting the role of lipids in the vascular damage associated with DR, including the DCCT/EDIC, ACCORD, Blue Mountain Eye Study and WESDR studies, suggest that retinal lipid levels may be more critical than circulating lipid levels. DR is not only the result of endothelial damage but also inadequate vascular repair. Dyslipidemia adversely impacts vascular repair by deleteriously affecting circulating angiogenic cells (CACs), a reparative bone marrow-derived (BMD) cell population. Dyslipidemia also promotes a proinflammatory environment in the retina and activates BMD inflammatory cells in particular monocytes. Thus, systemic and retinal lipid abnormalities simultaneously reduce vascular repair and also promote vascular damage by increasing inflammation. In this application, we provide insight into DR pathogenesis by examining a novel axis that unifies key lipid regulators, SIRT1 and liver X receptor (LXRa/LXRß). SIRT1, a member of the sirtuin family of NAD-dependent protein deacetylases, is decreased in DR. The beneficial effects of SIRT1 on metabolism and inflammation were shown to be mediated through LXR activation. Previously, we showed that pharmacological activation of liver X receptor (LXRa/LXRß) prevents DR in rodent models. In this proposal, we test the hypothesis that diabetes-induced disruption of the SIRT1-LXR axis results in abnormal lipid metabolism and inflammation. Strategies to stimulate this axis will result in activation of cellular and tissue cholesterol removal with normalization o cholesterol homeostasis and repression of the inflammatory genes, iNOS, IL-1ß, ICAM-1, and CCL2, in target tissues (retina) and cells (CACs and monocytes/macrophages). We put forth the following specific aims: Aim 1: To determine if activation of the SIRT1-LXR axis reverses diabetes-induced retinal damage through normalization of cholesterol homeostasis and reduction in iNOS, IL-1ß, ICAM- 1, and CCL2 inflammatory gene expression in the retina. Aim 2: To examine whether activation of the SIRT1-LXR axis reverses the diabetes-induced dysfunction of CACs and improves their reparative function by correcting CAC membrane fluidity towards normal to enhance migration out of the bone marrow (BM) and into areas of retinal injury and promote vascular repair. Aim 3: To determine whether activation of the SIRT1-LXR axis regulates the innate immune response resulting in a correction of diabetes-induced monocytosis and modulation of local and systemic macrophage/monocyte polarization.