Eicosanoids and Diabetic Retinopathy

描述(申请人提供)：糖尿病视网膜病变是导致视力丧失的主要原因，最近的证据表明炎症样过程和毛细血管细胞死亡在视网膜病变的发病机制中起着重要作用。花生四烯酸通过环氧合酶和脂氧合酶途径的代谢产物，统称为二十烷基类化合物，是已知的炎症介质。这项资助研究了二十烷基类化合物在糖尿病视网膜病变发病机制中的作用。候选人的初步数据表明，脂氧合酶和环氧合酶抑制剂都可以改善培养的视网膜内皮细胞中高糖诱导的细胞死亡。本研究分析了二十烷基硫酸酯途径中的三种主要酶，脂氧合酶(特异性靶点1)、环氧合酶(特异性靶点2)和磷脂酶A2(特异性靶点3)在高血糖诱导的毛细血管细胞死亡和其他视网膜病变的发病机制中的意义。将使用体外和体内技术。实验将比较糖尿病和非糖尿病基因敲除小鼠(即5-和12-脂氧合酶、环氧合酶-2或胞浆磷脂酶A2基因敲除)与野生型小鼠在视网膜病变发展和基于机制的生化参数(如二十烷类化合物；氧化应激；细胞因子和细胞死亡酶)方面的变化。国际公认的糖尿病视网膜病变研究员、糖尿病研究中心主任蒂莫西·克恩博士将指导候选人，并提供视网膜病理和动物模型方面的专家培训。该中心将向糖尿病领域的主要研究人员提供必要的技能，以帮助该项目的候选人。与二十烷类化合物研究领域的领先者曾傑瑞·纳德勒博士和约瑟夫·邦文特尔博士的合作将提供更多的专业知识。这种激励的环境，加上候选人对研究的奉献精神，以及儿科系的支持，构成了候选人实现作为一名儿科内分泌学家的研究独立性目标的基础。

DESCRIPTION (provided by applicant): Diabetic retinopathy is the leading cause of visual loss, and recent evidence suggests that inflammatory-like processes and capillary cell death play important roles in the pathogenesis of the retinopathy. Metabolites of arachidonic acid via the cyclooxygenase and lipoxygenase pathways, collectively known as eicosanoids, are known mediators of inflammation. This grant examines the role of eicosanoids in the pathogenesis of diabetic retinopathy. The candidate's preliminary data suggest that both lipoxygenase and cyclooxygenase inhibitors can ameliorate the high glucose-induced cell death seen in cultured retinal endothelial cells. This proposal dissects the significance of three major enzymes in the eicosanoid pathway, lipoxygenase (Specific Aim 1), cyclooxygenase (Specific Aim 2), and phospholipase A2 (Specific Aim 3), in the pathogenesis of hyperglycemia-induced death of capillary cells and other lesions of retinopathy. In vitro and in vivo techniques will be used. Experiments will compare diabetic and nondiabetic knockout mice (i.e., 5- and 12-lipoxygenase, cyclooxygenase-2 or cytosolic phospholipase A2 knockouts) to wild-type mice for alterations in development of retinopathy and mechanism-based biochemical parameters (e.g., eicosanoids; oxidative stress; cytokines; and cell death enzymes). Dr. Timothy Kern, an internationally-recognized investigator of diabetic retinopathy and director of the Center for Diabetes Research, will mentor the candidate and provide expert training in retinal pathology and animal models. The Center will provide exposure to leading investigators in diabetes with the necessary skills to assist the candidate in this project. Collaborations with Dr. Jerry Nadler and Dr. Joseph Bonventre, both leaders in the field of eicosanoid research, will provide additional expertise. This stimulating environment, along with the candidate's dedication to research, and the support of the Department of Pediatrics form a foundation for the candidate to achieve her goal of research independence as a pediatric endocrinologist.