Acetylation and diabetic retinopathy

描述(由申请人提供)： 糖尿病损害视网膜，由此导致的糖尿病视网膜病变(DR)是导致工作年龄成年人视力受损和失明的主要原因。尽管如此，DR的发病机制仍知之甚少。我们和其他人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，我们目前的Merit研究表明，高血糖诱导这些炎性蛋白的过程受蛋白质乙酰化的调节。我们目前建议的中心假设是糖尿病患者蛋白质乙酰化程度增加导致视网膜毛细血管退化。 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起着关键作用。使用两种DR模型(链脲佐菌素诱导1型糖尿病，以及自发性糖尿病db/db小鼠，这是2型糖尿病的模型)，这项建议中的研究将确定系统地抑制这种乙酰化蛋白(目标1)或仅在白细胞中抑制(目标2)是否抑制早期DR特有的血管病变的发展。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将把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防止白细胞介导的糖尿病视网膜内皮细胞的杀伤。我们还将开始探索糖尿病患者白细胞对视网膜内皮细胞的乙酰化介导的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发展为晚期DR。

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.