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.

项目摘要糖尿病性视网膜病（DR）是糖尿病的微血管并发症，是不可逆转的视力的主要原因美国人的损失。随着糖尿病的美国人人数继续攀升，流行率预计协调的博士有望上升。当前的DR治疗疗法仅在发生了无法弥补的视网膜损害，突出了需要进行治疗干预措施以防止早期进展。自1960年代以来，已经假设视网膜注射可能会提早驱动环氧酶（COX）依赖性方式中的DR进展。但是，各种非甾体抗抗的试验炎症药（NSAIDS）抑制COX作为DR治疗的抑制作用，在很大程度上失败了这些与慢性，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/或他们的接收者可以提供一种治疗方法，以隔离抗炎益处，同时避免 NSAID的严重副作用。在Cox途径中产生了五个前列腺素，通过九个发出信号前列腺素受体。这里提出的研究的目的是确定抑制单个前列腺素信号传导，以减慢DR发作和进展。我的初步研究有确定五个前列腺素中的两个（PGE2和PGF2α）在原代人类永久细胞中升高在与糖尿病有关的血脂异常或炎症的疾病中培养。 PGE2在Müller神经胶质中升高负责维持视网膜中的体内稳态，并且在视网膜微血管中PGF2α升高内皮细胞，形成残留的血管。我假设这两个前列腺素是关键的驱动因素促炎细胞因子产生和白细胞症，与Dr相关的标志性病理。这提案扩大了这些发现，以定义条件下的视网膜前列腺素海拔的景观与全身性糖尿病有关，并确定小分子前列腺素受体的临床前效率反对者是针对DR进展的有针对性治疗策略。我建议使用主要人 Müller神经胶质和视网膜微血管内皮细胞的培养以及糖尿病小鼠模型询问与细胞和基于动物的疾病相关的实验性的前列腺素信号传导的拮抗作用型号。在完成这些研究时，我旨在表征一种新型的治疗策略，以精确靶向在不可逆的早期DR之前可能驱动视网膜血管感染的分子信号通路发生损害。我将在约翰·佩恩博士的实验室的支持心理环境中进行工作在范德比尔特大学（Vanderbilt University 典范研究生培训的历史。该提案中概述的培训计划与我的研究配对目标将有助于我的培训成为一名独立的学术研究科学家。