Targeted prostanoid inhibition as an anti-inflammatory therapy for diabetic retinopathy

项目总结 糖尿病视网膜病变是糖尿病的一种微血管并发症，是导致视力不可逆的主要原因。 美国适龄劳动人口的损失。随着美国糖尿病患者数量的持续攀升，糖尿病的患病率 预计DR的比例将协调上升。目前治疗糖尿病视网膜病变的方法只治疗晚期糖尿病 视网膜已经发生了不可修复的损害，突显了需要治疗性干预来预防 早期进展。自20世纪60年代以来，人们一直假设视网膜炎症可能会导致早期 DR以环氧合酶(COX)依赖的方式进展。然而，各种非类固醇抗肿瘤药物的试验 抑制COX作为DR治疗的炎性药物(NSAIDs)在很大程度上是由于严重的 与慢性广谱COX抑制相关的心血管或胃肠道副作用 毒品。或者，靶向特定的前列腺素-COX下游的脂质信号分子-和/或 它们的受体可以提供一种治疗方法，在分离抗炎益处的同时避免 非甾体抗炎药的严重副作用。在COX途径中产生了五种前列腺素，通过九种途径传递信号 前列腺素受体。在这里提出的研究的目标是确定治疗潜力 抑制个体前列腺素信号以减缓DR的发生和进展。我的初步研究已经 五种前列腺素中的两种--前列腺素E_2和前列腺素F_2α--在原代人视网膜细胞中升高 在与糖尿病相关的血脂异常或炎症条件下培养。前列腺素E_2在Müler神经胶质细胞中升高 负责维持视网膜内的动态平衡，视网膜微血管中的前列腺素F2α升高 形成视网膜血管的内皮细胞。我推测这两个前列腺素是关键的驱动因素 促炎细胞因子的产生和白血球的淤滞，这是与Dr.This相关的标志性病理 建议在这些发现的基础上扩展，以定义在以下条件下视网膜前列腺样隆起的景观 与全身性糖尿病相关，并确定小分子前列腺素受体的临床前疗效 拮抗剂作为针对DR进展的靶向治疗策略。我建议利用原始人 Müler胶质细胞和视网膜微血管内皮细胞的培养以及糖尿病小鼠模型 细胞和动物疾病相关实验中前列腺素信号的询问拮抗作用 模特们。在完成这些研究时，我的目标是描述一种新的治疗策略，以精确地靶向 不可逆性糖尿病视网膜病变早期视网膜血管炎症的分子信号通路 损害就会发生。我将在约翰·潘博士实验室的支持性指导环境中开展我的工作 在范德比尔特大学，该研究所在前列腺素和视觉研究方面都有丰富的支持，并有很长的 模范研究生训练史。这份建议中概述的培训计划，与我的研究相匹配 目标，将对我成为一名独立的学术研究科学家的培训有极大的帮助。

PROJECT SUMMARY Diabetic retinopathy (DR), a microvascular complication of diabetes, is the leading cause of irreversible vision loss in working-age Americans. As the number of Americans with diabetes continues to climb, the prevalence of DR is expected to rise in coordination. Current therapies for DR treat only late stages of disease after irreparable damage to the retina has occurred, highlighting the need for therapeutic interventions to prevent early-stage progression. Since the 1960s, it has been hypothesized that retinal inflammation may drive early DR progression in a cyclooxygenase (COX)-dependent manner. However, trials of various nonsteroidal anti- inflammatory drugs (NSAIDs) to inhibit COX as a DR treatment have failed in large part due to severe cardiovascular or gastrointestinal side effects associated with chronic, broad-spectrum COX inhibition by these drugs. Alternatively, targeting specific prostanoids—the lipid signaling molecules downstream of COX—and/or their receptors could offer a therapeutic approach that isolates anti-inflammatory benefits while avoiding the severe side effects of NSAIDs. Five prostanoids are generated in the COX pathway, signaling through nine prostanoid receptors. The goal of the research proposed here is to determine the therapeutic potential of inhibiting individual prostanoid signaling to slow DR onset and progression. My preliminary studies have identified that two of the five prostanoids—PGE2 and PGF2α—are elevated in primary human retinal cells cultured in conditions of dyslipidemia or inflammation relevant to diabetes. PGE2 is elevated in Müller glia, cells responsible for maintaining homeostasis in the retina, and PGF2α is elevated in retinal microvascular endothelial cells, which form retinal blood vessels. I hypothesize that these two prostanoids are critical drivers of proinflammatory cytokine production and leukostasis, hallmark pathologies associated with DR. This proposal expands upon these findings to define the landscape of retinal prostanoid elevation under conditions relevant to systemic diabetes and to determine the preclinical efficacy of small molecule prostanoid receptor antagonists as targeted therapeutic strategies against DR progression. I propose utilizing primary human cultures of Müller glia and retinal microvascular endothelial cells as well as a diabetic mouse model to interrogate antagonism of prostanoid signaling in both cell- and animal-based disease-relevant experimental models. In completing these studies, I aim to characterize a novel therapeutic strategy to precisely target molecular signaling pathways that may drive retinal vascular inflammation in early-stage DR before irreversible damage occurs. I will carry out my work in the supportive mentoring environment of Dr. John Penn’s laboratory at Vanderbilt University, an institute with rich support of both prostanoid and vision research and with a long history of exemplary graduate training. The training plan outlined in this proposal, paired with my research goals, will aid invaluably in my training to become an independent academic research scientist.