Acetylation and diabetic retinopathy

描述（由申请人提供）： 糖尿病损害视网膜，并且所导致的糖尿病视网膜病变（DR）是工作年龄成人中视力损害和失明的主要原因。尽管如此，DR的发病机制仍知之甚少。我们和其他人所做的研究强烈暗示炎症过程在DR的关键微血管病变的发展中，并且我们目前的Merit研究期间所做的工作表明，高血糖对这些炎症蛋白的诱导受蛋白乙酰化的调节。我们目前建议的中心假设是糖尿病中蛋白质的乙酰化增加导致视网膜毛细血管变性 通过炎症途径，并且白细胞特别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关键作用。使用2种DR型号（诱导1型糖尿病的链脲霉素，和作为2型糖尿病模型的自发性糖尿病db/db小鼠），这项研究将确定是否抑制这种乙酰化系统（目标1）或仅在白细胞（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。该提案的第三个目的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）的白细胞来确定糖尿病中白细胞介导的视网膜内皮细胞杀伤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。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.