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：
9033384
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/9033384
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 Equilibrium Erythrocytes Event Eye diseases Fatty Acids Fatty-acid synthase Fenofibrate Functional disorder Genetic Transcription Glucose Goals Health Services Accessibility Human 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 Pathogenesis Pathologic Pathway interactions Patients Peroxisome Proliferator-Activated Receptors Phospholipid Metabolism Phospholipids Physicians Play Population Prevention Prevention strategy Process Production Protective Agents Public Health Retina Retinal Retinal Diseases Risk Role Safety Sampling Scientist Seminal Series Serum Signal Transduction Skeletal Muscle Staging Techniques Testing Therapeutic Tissues Vision Visual Work base blood lipid catalyst diabetic disability glycemic control high risk human subject improved lipid biosynthesis lipid metabolism mortality novel peripheral blood public health relevance receptor expression research study response retinal damage tool type I and type II diabetes

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（由适用提供）：糖尿病并发症的视力丧失在世界各地的发展中国家和我国的各个人口中都以猛烈的速度增长。更好地预防人口的巨大障碍是对疾病早期病原机制的基本理解。尽管当前的方法以降低血清葡萄糖为中心，但脂质异常在该疾病中的作用在很大程度上被忽略了。开创性的大型临床试验表明，非诺贝特对视网膜病的有益作用糖尿病的进展。该作用与循环脂蛋白水平无关。非诺贝特是过氧化物增生剂激活受体（PPAR）的配体。通过与包括磷脂在内的各种脂质结合，该转录面可作为细胞对营养状况的细胞反应的协调。从头脂肪生成（DNL），脂肪酸合酶（FAS）的胰岛素敏感催化剂是多次提供特定的磷脂配体向PPAR提供的，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症与2型糖尿病中胰岛素抵抗的新型潜在联系与在这两种情况下对视网膜的逐渐损害之间的胰岛素抵抗。在此应用中，我们概述了细胞培养系统和缺乏残留FA的动物的一系列实验，这些实验旨在了解DNL在健康和糖尿病性视网膜中的机制和功能。然后，我们提出了一项横断面研究，以识别患有糖尿病患者通过电子结构摄影发展视网膜病的高风险，这是一种非侵入性临床工具，我们在机构中广泛使用。在视网膜病的早期阶段的患者中，我们将测量已显示与视网膜磷脂高度相关的红细胞磷脂。总之，这些研究旨在建立系统性和视网膜磷脂代谢异常与糖尿病性视网膜病的早期功能异常之间的新联系。我们将测试相关的假设，即视网膜脂肪发生变化有助于糖尿病性视网膜病，并且外周血的脂质改变与糖尿病性视网膜早期ERG变化高度相关。为了实现这一目标，我们将解决以下三个目标：（1）定义FA在确定视网膜脂质代谢中的作用；（2）确定糖尿病动物中FAS的靶向缺失是否加剧了视网膜病变；（3）定义特定的红细胞磷脂特征，可能与早期糖尿病性视网膜病有关，使用基于质谱的人类受试者的外周血分析。通过我们机构的内分泌学家和眼科医生之间的伙伴关系，该应用有可能发现与早期糖尿病性视网膜病有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，我们可能会提供早期疾病的血液磷脂生物标志物，这些疾病可以鉴定出患有高风险的患者。易于记录的早期视网膜病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具有侵略性血糖控制的智慧必须通过对与这些措施相关的死亡率增加的担忧来平衡（23，24）。此外，由于目前的治疗方法不会改善许多患者的糖尿病眼病（25），并且由于对当前使用药物的安全性存在越来越多的担忧（26，27），因此基于脂质的疗法为这种棘手的疾病提供了一种有吸引力的替代方法。