LXR as a novel therapeutic target in diabetic retinopathy

LXR作为糖尿病视网膜病变的新型治疗靶点

• 批准号: 8987391
• 负责人: Michael Edwin Boulton
• 金额: $ 58.24万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8987391
• 关键词: Affect; Aging; Agonist; Area; Blood; Blood Vessels; Bone Marrow; CCL2 gene; Cell membrane; Cells; Cholesterol; Cholesterol Homeostasis; Clinical Research; Clinical Trials; Complication; Deacetylation; Development; Diabetes Mellitus; Diabetic Retinopathy; Diabetic mouse; Dyslipidemias; Environment; Excision; Eye; Family; Functional disorder; Gene Expression; Genes; Hepatocyte; Immune response; Inflammation; Inflammatory; Inflammatory Response; Injury; Intercellular adhesion molecule 1; Ligands; Link; Lipids; Liver; Mediating; Membrane Fluidity; Metabolic; Metabolic syndrome; Metabolism; Microvascular Dysfunction; Monocytosis; Nuclear Hormone Receptors; Out-Migrations; Pathogenesis; Pharmacotherapy; Play; Population; Prevention approach; Proteins; Repression; Retina; Retinal; Rodent Model; Role; Sir2-like Deacetylases; Skeletal Muscle; Testing; Tissues; clinically relevant; diabetic; drug development; falls; gain of function; improved; insight; lipid metabolism; loss of function; macrophage; macrovascular disease; member; monocyte; mouse model; new therapeutic target; novel; novel strategies; prevent; public health relevance; receptor; repaired; retinal damage; sensor; uptake

 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.

 描述（由申请人提供）：临床研究支持脂质在与 DR 相关的血管损伤中的作用，包括 DCCT/EDIC、ACCORD、蓝山眼科研究和 WESDR 研究，表明视网膜脂质水平可能比循环脂质更重要DR 水平不仅是内皮损伤的结果，而且血脂异常也会通过有害地影响循环血管生成细胞 (CAC) 来影响血管修复。修复性骨髓源性 (BMD) 细胞群也会促进视网膜中的促炎环境，并激活 BMD 炎症细胞，特别是单核细胞，因此，全身性和视网膜脂质异常会同时减少血管修复，并通过增加炎症来促进血管损伤。在该应用中，我们通过检查统一关键脂质调节因子 SIRT1 和肝脏 X 受体 (LXRa/LXRß) 的新轴来深入了解 DR 发病机制。 SIRT1 是 NAD 依赖性蛋白脱乙酰酶家族的成员，在 DR 中减少。 SIRT1 对代谢和炎症的有益作用被证明是通过 LXR 激活介导的。 LXRa/LXRß）可预防啮齿类动物模型中的 DR 在本提案中，我们测试了糖尿病诱导的 SIRT1-LXR 轴破坏导致脂质代谢异常和的假设。刺激该轴的策略将导致细胞和组织胆固醇清除的激活，使胆固醇稳态正常化，并抑制靶组织（视网膜）和细胞中的炎症基因、iNOS、IL-1ß、ICAM-1 和 CCL2。 （CAC 和单核细胞/巨噬细胞）。我们提出了以下具体目标： 目标 1：确定 SIRT1-LXR 轴的激活是否可以逆转糖尿病引起的视网膜。通过胆固醇稳态正常化和视网膜中 iNOS、IL-1ß、ICAM-1 和 CCL2 炎症基因表达的减少来减轻损伤。 目标 2：检查 SIRT1-LXR 轴的激活是否可以逆转糖尿病引起的 CAC 和 CAC 功能障碍。通过将 CAC 膜流动性纠正为正常来增强其从骨髓 (BM) 迁移到视网膜损伤区域并促进血管修复，从而改善其修复功能。目标 3：确定 SIRT1-LXR 轴的激活是否调节先天免疫反应，从而纠正糖尿病诱导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。