Acetylation and diabetic retinopathy

乙酰化与糖尿病视网膜病变

• 批准号: 8974329
• 负责人: Timothy S Kern
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8974329
• 关键词: Acetylation; Adult; Age; Animals; Blindness; Blood Vessels; Blood capillaries; Bone Marrow; Cells; Characteristics; Contrast Sensitivity; Developed Countries; Development; Diabetes Mellitus; Diabetic Retinopathy; Endothelial Cells; Genes; Glucose; Health; Histone Acetylation; Hyperglycemia; In Vitro; Inflammation; Inflammatory; Insulin-Dependent Diabetes Mellitus; Intervention Trial; Investigation; Lesion; Leukocytes; Mediating; Modeling; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Play; Prevention trial; Process; Protein Acetylation; Proteins; Research; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Role; Severities; Staging; Streptozocin; Testing; Time; Veterans; Vision; Visual Acuity; Visual impairment; Work; aged; capillary; db/db mouse; diabetic; diabetic patient; experience; glycemic control; improved; killings; non-diabetic; novel; novel strategies; prevent; relating to nervous system

DESCRIPTION (provided by applicant): Diabetes damages the retina, and the resulting diabetic retinopathy (DR) is the leading cause of visual impairment and blindness in working-aged adults. Despite this, the pathogenesis of DR is poorly understood. Research done by us and others strongly implicates inflammatory processes in the development of the critical microvascular lesions of DR, and work done during our current Merit research demonstrates that the induction of these inflammatory proteins by hyperglycemia is regulated by protein acetylation. The central hypothesis of our current proposal is that increased acetylation of proteins in diabetes contribute to the degeneration of retinal capillaries via inflammatory pathways, and that leukocytes in particular play a critical role in the pathogenesis of this acetylation-driven degeneration of retinal capillaries. Using 2 models of DR (streptozotocin to induce a Type 1 diabetes, and spontaneously diabetic db/db mice which are a model of Type 2 diabetes), research in this proposal will determine if inhibition of this acetylatin systemically (Aim 1) or in leukocytes only (Aim 2) inhibits development of the characteristic vascular lesions of early DR. These studies will be performed both as prevention trials and as intervention trials. The third aim of this proposal will extend these studies to patients, using leukocytes from Veterans (both diabetic and nondiabetic) to determine if leukocyte- mediated killing of retinal endothelial cells in diabetes can be prevented by inhibiting or reversing acetylation of proteins in leukocytes. We also will begin to explore if the extent of acetylation-mediated killing of retinal endothelial cells by leukocytes from diabetic patients correlates with the severity of retinopathy and might predict which patients are most susceptible to develop advanced DR.

描述（由申请人提供）： 糖尿病会损害视网膜，由此引起的糖尿病视网膜病变 (DR) 是导致工作年龄成人视力障碍和失明的主要原因。尽管如此，人们对 DR 的发病机制仍知之甚少。我们和其他人所做的研究强烈表明炎症过程与 DR 关键微血管病变的发展有关，并且我们当前的 Merit 研究期间所做的工作表明，高血糖诱导这些炎症蛋白受到蛋白乙酰化的调节。我们当前提案的中心假设是，糖尿病中蛋白质乙酰化的增加会导致视网膜毛细血管的变性 通过炎症途径，白细胞在这种乙酰化驱动的视网膜毛细血管变性的发病机制中尤其发挥着关键作用。使用 2 种 DR 模型（诱导 1 型糖尿病的链脲佐菌素和作为 2 型糖尿病模型的自发性糖尿病 db/db 小鼠），本提案中的研究将确定是否对这种乙酰化酶进行全身抑制（目标 1）或白细胞抑制仅（目标 2）抑制早期 DR 特征性血管病变的发展。这些研究将作为预防试验和干预试验进行。该提案的第三个目标是将这些研究扩展到患者，使用退伍军人（糖尿病和非糖尿病）的白细胞来确定是否可以通过抑制或逆转白细胞中蛋白质的乙酰化来预防糖尿病中白细胞介导的视网膜内皮细胞杀伤。我们还将开始探索糖尿病患者白细胞乙酰化介导的视网膜内皮细胞杀伤程度是否与视网膜病变的严重程度相关，并可能预测哪些患者最容易患上晚期 DR。