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（由申请方提供）：支持脂质在DR相关血管损伤中作用的临床研究，包括DCCT/EDIC、雅阁、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水平更重要。DR不仅是内皮损伤的结果，也是血管修复不充分的结果。血脂异常通过有害地影响循环血管生成细胞（CAC）（一种修复性骨髓源性（BMD）细胞群）而对血管修复产生不利影响。血脂异常还促进视网膜中的促炎环境并激活BMD炎性细胞，特别是单核细胞。因此，全身和视网膜脂质异常同时减少血管修复，并通过增加炎症促进血管损伤。在本申请中，我们通过检查一种新的轴来深入了解DR发病机制，该轴将关键脂质调节剂SIRT 1和肝脏X受体（LXR α/LXR β）统一起来。SIRT 1是NAD依赖性蛋白脱乙酰酶sirtuin家族的成员，在DR中减少。SIRT 1对代谢和炎症的有益作用显示通过LXR激活介导。以前，我们表明，药理学激活肝脏X受体（LXR α/LXR β）预防啮齿动物模型中的DR。在这个提议中，我们测试了糖尿病诱导的SIRT 1-LXR轴破坏导致脂质代谢异常和炎症的假设。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（CAC和单核细胞/巨噬细胞）中的炎症基因iNOS、IL-1 β、ICAM-1和CCL 2。我们提出了以下具体目的：目的1：确定SIRT 1-LXR轴的激活是否通过胆固醇稳态的正常化和视网膜中iNOS、IL-1 β、ICAM- 1和CCL 2炎性基因表达的减少来逆转糖尿病诱导的视网膜损伤。目标二：研究SIRT 1-LXR轴的激活是否逆转糖尿病诱导的CAC功能障碍，并通过将CAC膜流动性校正至正常水平以增强从骨髓（BM）迁移到视网膜损伤区域并促进血管修复来改善其修复功能。目标三：确定SIRT 1-LXR轴的激活是否调节先天性免疫应答，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。