EARLY DETECTION OF DIABETIC RETINOPATHY BY PERIPHERAL BLOOD LIPID PROFILING

通过外周血脂分析早期检测糖尿病视网膜病变

基本信息

批准号：
9197299
负责人：
Rithwick Rajagopal
金额：
$ 19.61万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9197299
关键词：
Address Adipose tissue Agonist American Animal Model Animals Binding Biological Markers Blindness Blood Blood Tests Caring Cell Culture System Cells Central Nervous System Diseases Clinical Clinical Trials Complications of Diabetes Mellitus Country Cross-Sectional Studies Defect Detection Developing Countries Development Diabetes Mellitus Diabetic Retinopathy Diagnostic Disease Early Diagnosis Early Intervention Electroretinography Endocrinologist Environment Erythrocytes Event Eye diseases Fatty Acids Fatty-acid synthase Fenofibrate Functional disorder Glucose Goals Health Services Accessibility Human Impairment Improve Access Incidence Institution Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Ligands Link Lipids Lipoproteins Liver Mass Spectrum Analysis Measures Mediating Metabolic Methods Microvascular Dysfunction Modeling Non-Insulin-Dependent Diabetes Mellitus Nutritional status Ophthalmologist Ophthalmoscopy PPAR alpha Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Peroxisome Proliferator-Activated Receptors Phospholipid Metabolism Phospholipids Physicians Physiological Play Population Prevention Prevention strategy Production Protective Agents Public Health Retina Retinal Retinal Diseases Risk Role Safety Sampling Scientist Seminal Series Serum Signal Transduction Skeletal Muscle Techniques Testing Therapeutic Tissues Vision Visual Work base blood lipid catalyst cost diabetic disability experimental study glycemic control high risk human subject improved lipid biosynthesis lipid metabolism mortality novel peripheral blood public health relevance receptor expression response retinal damage tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): Vision loss from complications of diabetes is growing at a fierce rate in developing nations around the world and in various populations in our country. A tremendous obstacle to better population-wide prevention is a basic understanding of the early pathogenic mechanisms of the disease. While current approaches are centered on lowering serum glucose, the roles that lipid abnormalities play in this disease have largely been ignored. Seminal large clinical trials have shown a beneficial effect of fenofibrate on retinopathy progression in diabetes. The effect was independent of circulating lipoprotein levels. Fenofibrate is a ligand for peroxisome proliferator-activated receptor  (PPAR). This transcription facor acts as a coordinator of cellular responses to nutritional status by binding to various lipids, including phospholipids. An insulin-sensitive catalyst of de novo lipogenesis (DNL), Fatty Acid Synthase (FAS), is required for the provision of specific phospholipid ligands to PPARs in multiple tissues, but has not yet been studied in the retina. This pathway represents a novel potential link between insulin deficiency in Type 1 diabetes or insulin resistance in Type 2 diabetes and progressive damage to the retina in both of these conditions. In this application, we outline a series of experiments in cell culture systems and in animals lacking retinal FAS that are aimed at understanding mechanisms and functions of DNL in the healthy and diabetic retina. We then propose a cross-sectional study to identify people with diabetes at high risk for developing retinopathy through electroretinography, a non-invasive clinical tool that we use extensively at our institution. In patients with this early stage of retinopathy, we will measure erythrocyte phospholipids that have been shown to correlate highly with retinal phospholipids. Together, these studies are aimed at establishing a novel link between abnormalities in systemic and retinal phospholipid metabolism and early functional abnormalities in diabetic retinopathy. We will test the related hypotheses that changes in retinal lipogenesis contribute to diabetic retinopathy and that lipid alterations in peripheral blood are highly correlated with earl ERG changes in the diabetic retina. Towards this goal, we will address the following three aims: (1) To define roles for FAS in regulating retinal lipid metabolism; (2) To determine if targeted deletion of FAS exacerbates retinopathy in diabetic animals; (3) To define specific erythrocyte phospholipid profiles that may be associated with early diabetic retinopathy using a mass spectrometry-based analysis of peripheral blood from human subjects. Through a partnership between endocrinologists and ophthalmologists at our institution, this application has the potential to uncover early pathologic changes in lipid metabolism associated with early diabetic retinopathy, which may have important diagnostic and therapeutic implications. Through our studies, we may deliver blood-based phospholipid biomarkers of early disease that could identify patients who are at high risk for progression. An easily recorded blood-based indicator of early retinopathy may also improve access to care. Prevailing wisdom surrounding prevention of microvascular disease with aggressive glycemic control must be balanced by concerns for increased mortality associated seen with these measures (23, 24). Moreover, because current treatments do not ameliorate diabetic eye disease in many patients (25) and because there are increasing concerns with the safety of currently-used agents (26, 27), lipid-based therapies offer an attractive alternative approach to therapy for this intractable disease.

描述（由申请人提供）：在世界各地的发展中国家和我国的不同人群中，糖尿病并发症引起的视力丧失正在以惊人的速度增长，而对早期致病因素的基本了解是更好地进行全民预防的一个巨大障碍。虽然目前的方法集中于降低血糖，但脂质异常在该疾病中所起的作用在很大程度上被忽视了，开创性的大型临床试验表明非诺贝特对视网膜病变具有有益作用。其作用是循环脂蛋白水平的独立进展。该转录因子通过与各种脂质（包括磷脂）结合，充当细胞对营养状态反应的协调剂。从头脂肪生成 (DNL) 的胰岛素敏感催化剂脂肪酸合成酶 (FAS) 是提供特定磷脂配体所必需的PPAR 存在于多个组织中，但尚未在视网膜中进行研究。该途径代表了 1 型糖尿病中的胰岛素缺乏或 2 型糖尿病中的胰岛素抵抗与这两种情况下视网膜进行性损伤之间存在新的潜在联系。在应用中，我们概述了在细胞培养系统和缺乏视网膜 FAS 的动物中进行的一系列实验，旨在了解 DNL 在健康和糖尿病视网膜中的机制和功能，然后我们提出了一项横断面研究来识别糖尿病患者。发展风险通过视网膜电图检查，这是我们机构主要使用的一种非侵入性临床工具，我们将测量与视网膜磷脂高度相关的红细胞磷脂。在全身和视网膜磷脂代谢异常与糖尿病视网膜病变的早期功能异常之间建立新的联系我们将测试视网膜脂肪生成的变化导致的相关假设。糖尿病视网膜病变以及外周血脂质变化与糖尿病视网膜早期 ERG 变化高度相关。为了实现这一目标，我们将实现以下三个目标：（1）确定 FAS 在调节视网膜脂质代谢中的作用；确定 FAS 的靶向删除是否会加重糖尿病动物的视网膜病变 (3) 使用肿块来确定可能与早期糖尿病视网膜病变相关的特定红细胞磷脂谱；通过我们机构的内分泌学家和眼科医生之间的合作，该应用程序有可能揭示与早期糖尿病视网膜病变相关的脂质代谢的早期病理变化，这可能具有重要的诊断和治疗意义。通过我们的研究，我们可以提供早期疾病的血液磷脂生物标志物，可以识别进展风险较高的患者。易于记录的早期视网膜病变的血液指标也可以改善获得护理的机会。围绕预防微血管疾病和积极控制血糖必须与这些措施相关的死亡率增加的担忧相平衡 (23, 24) 此外，因为目前的治疗方法并不能改善许多患者的糖尿病眼病 (25)，而且糖尿病眼病的发病率也在增加。考虑到目前使用的药物的安全性 (26, 27)，基于脂质的疗法为治疗这种顽固性疾病提供了一种有吸引力的替代方法。