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（由适用提供）：支持脂质在与DR相关的血管损伤中的作用的临床研究，包括DCCT/EDIC，Accord，Blue Mountain Eye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为重要。 DR不仅是内皮损害的结果，而且是血管修复不足的结果。血脂异常不利地影响了有害的血管生成细胞（CAC）的血管修复，这是一种修复骨髓衍生的（BMD）细胞群。血脂异常还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。这是系统性和视网膜脂质异常仅减少血管修复，也通过增加炎症来促进血管损伤。在此应用中，我们通过检查一个新的轴，该轴统一了关键的脂质调节剂SIRT1和肝X受体（LXRA/LXRß），从而提供了对DR发病机理的见解。 SIRT1是NAD依赖性蛋白脱乙酰基酶Sirtuin家族的成员，在DR中得到了改善。 SIRT1对代谢和炎症的有益作用被证明是通过LXR激活介导的。以前，我们表明肝脏X受体（LXRA/LXRß）的药物激活可防止啮齿动物模型中的DR。在此提案中，我们检验了以下假设：糖尿病诱导的SIRT1-LXR轴的破坏会导致异常的脂质代谢和注射。刺激该轴的策略将导致细胞和组织胆固醇的去除，并通过正常化的O胆固醇稳态以及在靶向时间（视网膜）和细胞（CAC和单核细胞/单噬细胞）中的炎症基因，INOS，IL-1ß，ICAM-1和CCL2的反射。我们提出了以下具体目的：目标1：确定SIRT1-LXR轴的激活是否通过胆固醇稳态的归一化以及Inos，IL-1ß，ICAM-1-1和CCL2炎症基因表达在视网膜中逆转糖尿病引起的视网膜损伤。目标2：检查SIRT1-LXR轴的激活是否会逆转糖尿病诱导的CAC功能障碍，并通过纠正CAC膜流动性向正常的CAC膜流动性提高其修复功能，从而增强从骨髓（BM）和视网膜损伤区域迁移并促进血管造成的迁移。目标3：确定SIRT1-LXR轴的激活是否调节先天免疫响应，从而纠正糖尿病诱导的单核细胞增多症以及对局部和全身性巨噬细胞/单核细胞极化的调节。