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

靶向前列腺素抑制作为糖尿病视网膜病变的抗炎治疗

基本信息

批准号：
10751497
负责人：
Amy Kathryn Stark
金额：
$ 3.3万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751497
关键词：
Address Adhesions Age American Animals Anti-Inflammatory Agents Biological Assay Blindness Blood Glucose Blood Vessels Cardiovascular system Cell Adhesion Molecules Cells Chronic Clinical Trials Complications of Diabetes Mellitus Cytokine Gene Data Diabetes Mellitus Diabetic Angiopathies Diabetic Retinopathy Diabetic mouse Dinoprostone Disease Dose Drug Targeting Drug usage Dyslipidemias Early Intervention Electroretinography Endothelial Cells Endothelium Environment Enzymes Event Exhibits Experimental Models Functional disorder Gene Expression Generations Glucose Goals Homeostasis Human ICAM1 gene Ibuprofen Impairment In Vitro Individual Inflammation Inflammatory Interleukin-1 beta Laboratories Leukocytes Leukostasis Lipids Mass Spectrum Analysis Measures Mentors Molecular Target Muller&apos s cell Mus Non-Steroidal Anti-Inflammatory Agents Nonesterified Fatty Acids Palmitic Acids Pathogenicity Pathology Pathway interactions Pharmaceutical Preparations Pharmacotherapy Prevalence Production Prostaglandin-Endoperoxide Synthase Prostaglandins Recording of previous events Research Retina SELE gene Scientist Signal Pathway Signal Transduction Signaling Molecule Stains Stimulus Streptozocin Testing Therapeutic Therapeutic Intervention Time Tissues Training Treatment Efficacy Triglycerides Universities Vascular Endothelial Cell Vision research Visual impairment Work antagonist blood damage cell behavior cell injury cytokine diabetic gastrointestinal immune cell infiltrate in vivo mouse model novel therapeutic intervention novel therapeutics pain reduction pre-clinical assessment preclinical efficacy prevent receptor retina blood vessel structure retinal damage side effect small molecule targeted treatment therapeutic evaluation therapeutic target vascular inflammation

项目摘要

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.

项目概要糖尿病视网膜病变 (DR) 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随着美国人患糖尿病的人数持续攀升，患病率也随之下降。预计 DR 的发病率将在协调中上升。目前的 DR 疗法仅治疗疾病的晚期。视网膜已发生不可挽回的损伤，突出表明需要采取治疗干预措施来预防自 20 世纪 60 年代以来，人们发现视网膜炎症可能导致早期进展。 DR 以环氧合酶 (COX) 依赖性方式进展。然而，各种非甾体抗药的试验。抑制 COX 的炎症药物 (NSAID) 作为 DR 治疗方法已失败，这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或者，靶向特定的前列腺素（COX 下游的脂质信号分子）和/或他们的受体可以提供一种治疗方法，在避免抗炎作用的同时， NSAID 的严重副作用是在 COX 途径中产生五种前列腺素，通过九种信号传导。这里提出的研究目标是确定前列腺素受体的治疗潜力。我的初步研究表明，抑制个体前列腺素信号传导可以减缓 DR 的发生和进展。发现五种前列腺素中的两种——PGE2 和 PGF2α——在原代人视网膜细胞中升高在血脂异常或与糖尿病相关的炎症条件下培养的 Müller 胶质细胞中 PGE2 升高。负责维持视网膜的稳态，PGF2α在视网膜微血管中升高我发现这两种前列腺素是关键的驱动因素。促炎细胞因子的产生和白细胞停滞，这是与 DR 相关的标志性病理。该提案扩展了这些发现，以定义条件下视网膜前列腺素升高的情况与全身糖尿病相关并确定小分子前列腺素受体的临床前疗效我建议使用主要的人类拮抗剂作为针对 DR 进展的靶向治疗策略。 Müller 胶质细胞和视网膜微血管内皮细胞培养物以及糖尿病小鼠模型在基于细胞和动物的疾病相关实验中探究前列腺素信号传导的拮抗作用在完成这些研究时，我的目标是描述一种新的治疗策略来精确靶向。可能在不可逆转的早期 DR 中驱动视网膜血管炎症的分子信号通路发生损坏时，我将在约翰·佩恩博士实验室的支持性指导环境中进行损坏损坏。在范德比尔特大学，该研究所在前列腺素和视觉研究方面拥有丰富的支持，并且拥有长期的研究经验。本提案中概述的培训计划与我的研究相结合。目标，将对我成为一名独立学术研究科学家的培训提供无价的帮助。