Neuroprotective strategies for retinopathy and cognition in diabetes

糖尿病视网膜病变和认知的神经保护策略

• 批准号: 10599862
• 负责人: RACHAEL STEWART ALLEN
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10599862
• 关键词: Acute Lung Injury; Adult; Age; Age Years; Angiogenesis Inhibition; Angiogenesis Inhibitors; Animal Model; Animals; Appearance; Area; Award; Blindness; Blood Vessels; Blood capillaries; Brain; Caring; Cerebrum; Clinical; Clinical Research; Clinical Trials; Cognition; Cognitive deficits; Complications of Diabetes Mellitus; Corpus striatum structure; Development; Diabetes Mellitus; Diabetic Retinopathy; Disease; Disease Progression; Dopamine; Dopamine Agonists; Dose; Electroretinography; Endocytosis; Environment; Enzyme-Linked Immunosorbent Assay; Exhibits; Extravasation; Fat-Restricted Diet; Foundations; Functional disorder; Future; Goals; Healthcare Systems; High Fat Diet; High Pressure Liquid Chromatography; Histology; Human; Hyperemia; Hyperglycemia; Impaired cognition; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Irritable Bowel Syndrome; KDR gene; Kidney; Levodopa; Link; Malignant Neoplasms; Measures; Medical Records; Memory Loss; Mental Depression; Modeling; Motivation; Motor; Neuronal Dysfunction; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Outcome Study; Pathology; Pathway interactions; Patients; Pericytes; Pharmaceutical Preparations; Population; Prevalence; Prevention; Productivity; Rattus; Recording of previous events; Research; Research Personnel; Retina; Retinal Diseases; Rodent; Rodent Model; Role; Scientist; Signs and Symptoms; Streptozocin; Structure; System; Time; Tissues; Training; Translating; Translations; Treatment Efficacy; Type 2 diabetic; Vascular Diseases; Vascular Endothelial Growth Factors; Veterans; brain dysfunction; brain health; brain tissue; career development; clinical application; clinical translation; clinically relevant; cognitive change; diabetic; diabetic patient; diabetic rat; interest; large datasets; motor deficit; motor disorder; neovascularization; neuroprotection; patient population; pre-clinical; prevent; restoration; retinal damage; side effect; visual dysfunction

Over 25 million U.S. citizens (8.3% of the population) have diabetes, including 20% of veterans in the VA system. With the worldwide prevalence of diabetes predicted to rise 35% by 2025, diabetic complications impose an ever-increasing burden on healthcare systems. One of the most common complications, diabetic retinopathy (DR), is the leading cause of blindness in working age adults. In addition, early neuronal dysfunction in diabetic retinopathy occurs prior to clinically diagnosable pathology, and early DR is likely intimately related to other diabetic complications, for example, cognitive decline and structural changes in the brain. The continued rise in the number of diabetic patients and the complexity of their care underscores the urgent need to identify clinically translatable treatments to target complications prior to obvious signs and symptoms. While diabetes is not commonly thought of as a disease of dopamine disruption, dopamine has been implicated in several diabetic complications, including diabetic retinopathy. Our approach is to identify whether dopamine deficiency is a common mechanism for cerebral and retinal deficits in Type II diabetes and to use this information to develop dopamine treatments for long term clinical translation that would delay disease progression. In this study, we will use the high fat diet + low dose STZ rat model of Type II diabetes because approximately 90% of diabetic patients in the VA system have Type II diabetes. We hypothesize that: 1) dopamine disruption underlies both retinal and cerebral complications in diabetes, and 2) dopamine- targeted treatments will result in reduced retinal, cognitive, and motor dysfunction and reduced vascular pathology in the brain and retina. In the first specific aim, we will identify in Type II diabetic rats the temporal appearance of retinal dysfunction (electroretinogram, optokinetic tracking), cognitive dysfunction (y-maze), motor dysfunction (rotarod), retinal vascular dysfunction (functional hyperemia), and later stage vascular pathology (acellular capillaries and pericyte loss), as well as retinal and brain levels of dopamine and DOPAC (HPLC). After determining the time course of these deficits, in the second specific aim, we will implement L- DOPA treatment to reduce dopamine deficiency in diabetic rats. We will determine whether rats receiving treatment exhibit reduced dopamine deficiency and reduced retinal, cognitive, and motor dysfunction. In our third specific aim, we will use a retrospective chart review in a large dataset to determine whether diabetic patients taking levodopa or dopamine agonists exhibit delayed onset and progression of DR compared with diabetic patients not taking dopamine-related drugs. The expected outcome of this study is that L-DOPA treatment given at the earliest signs of retinopathy in a rodent model of Type II diabetes will provide protection against diabetic damage in the brain and retina and that L-DOPA/dopamine agonists will provide similar protection against DR in patients. Our rodent research can lead to the identification of a similar window for preclinical retinopathy treatment in diabetic patients, which would allow for greater treatment efficacy and prevention of future complications. If treatments that target dopamine protect against retinal and cerebral complications in diabetes, these findings would motivate the development of a human clinical trial. Overall, the motivation for this study is the need for a better understanding of the role of dopamine in diabetic retinopathy and other diabetic complications with the long-term goal of developing dopamine-targeted treatments that delay or prevent vision loss and cerebral deficits in our Veterans and others with diabetes. The Atlanta VA has a large population of diabetic patients and already performs clinical diabetes research, making a long term clinical study on dopamine treatment in diabetes a natural fit for the Center’s goals and interests. This research will also provide valuable training to the applicant, which will enable her to become a successful and productive independent investigator in the field of the diabetic brain and retina within the VA research environment.

超过 2500 万美国公民（占总人口的 8.3%）患有糖尿病，其中包括 20% 的退伍军人 系统。预计到 2025 年，全球糖尿病患病率将上升 35%，糖尿病并发症 给医疗保健系统带来越来越重的负担。最常见的并发症之一是糖尿病 视网膜病变（DR）是工作年龄成年人失明的主要原因。此外，早期神经元 糖尿病视网膜病变的功能障碍发生在临床可诊断的病理之前，并且早期 DR 很可能 与其他糖尿病并发症密切相关，例如认知能力下降和大脑结构变化 脑。糖尿病患者数量的持续增加及其护理的复杂性凸显了 迫切需要在出现明显症状和症状之前确定可临床转化的治疗方法以针对并发症 症状。虽然糖尿病通常不被认为是多巴胺破坏的疾病，但多巴胺 与多种糖尿病并发症有关，包括糖尿病视网膜病变。我们的方法是识别 多巴胺缺乏是否是 II 型糖尿病患者大脑和视网膜缺陷的常见机制 利用这些信息来开发多巴胺治疗方法，以进行长期临床转化，从而延迟 疾病进展。本研究采用高脂饮食+低剂量STZ的II型糖尿病大鼠模型 因为 VA 系统中大约 90% 的糖尿病患者患有 II 型糖尿病。我们假设 认为：1）多巴胺破坏是糖尿病视网膜和大脑并发症的基础，2）多巴胺- 有针对性的治疗将减少视网膜、认知和运动功能障碍，并减少血管损伤 大脑和视网膜的病理学。在第一个具体目标中，我们将确定 II 型糖尿病大鼠的颞叶 出现视网膜功能障碍（视网膜电图、光动追踪）、认知功能障碍（y 迷宫）、 运动功能障碍（旋转）、视网膜血管功能障碍（功能性充血）和晚期血管功能障碍 病理学（无细胞毛细血管和周细胞损失），以及视网膜和大脑中多巴胺和 DOPAC 的水平 （高效液相色谱法）。确定这些赤字的时间进程后，在第二个具体目标中，我们将实施L- 多巴治疗可减少糖尿病大鼠的多巴胺缺乏。我们将确定大鼠是否接受 治疗表现出多巴胺缺乏的减少以及视网膜、认知和运动功能障碍的减少。在我们的 第三个具体目标，我们将在大型数据集中使用回顾性图表审查来确定是否患有糖尿病 与服用左旋多巴或多巴胺激动剂的患者相比，服用左旋多巴或多巴胺激动剂的患者 DR 的发病和进展延迟 糖尿病患者未服用多巴胺相关药物。本研究的预期结果是左旋多巴 在 II 型糖尿病啮齿动物模型中出现视网膜病变的最早迹象时给予治疗将提供保护 对抗糖尿病对大脑和视网膜的损害，左旋多巴/多巴胺激动剂将提供类似的作用 预防患者 DR。我们的啮齿动物研究可以识别出类似的窗口 糖尿病患者的临床前视网膜病变治疗，这将提高治疗效果 预防未来的并发症。如果针对多巴胺的治疗可以预防视网膜和脑损伤 糖尿病并发症，这些发现将推动人体临床试验的发展。总体而言， 这项研究的动机是需要更好地了解多巴胺在糖尿病视网膜病变中的作用 和其他糖尿病并发症，长期目标是开发多巴胺靶向治疗 延缓或预防退伍军人和其他糖尿病患者的视力丧失和脑部缺陷。亚特兰大 VA 有 大量的糖尿病患者，并且已经进行了临床糖尿病研究，做出了长期的研究 多巴胺治疗糖尿病的临床研究自然符合该中心的目标和兴趣。这项研究 还将为申请人提供宝贵的培训，使她能够成为一名成功且富有成效的人 VA 研究环境中糖尿病大脑和视网膜领域的独立研究者。