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

• 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
• 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

 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(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，糖尿病并发症导致的视力损失正在以惊人的速度增长。更好的全人群预防的一个巨大障碍是对疾病早期致病机制的基本了解。虽然目前的治疗方法主要集中在降低血糖上，但血脂异常在这种疾病中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有有益效果 糖尿病的进展。这种影响与循环脂蛋白水平无关。非诺贝特是过氧化物酶体增殖物激活受体(PPAR)的配体。这种转录因子通过与包括磷脂在内的各种脂类结合，作为细胞对营养状态的反应的协调器。胰岛素敏感的从头脂肪生成(DNL)催化剂--脂肪酸合成酶(Fas)是为多个组织中的PPAR提供特定磷脂配体所必需的，但尚未在视网膜中进行研究。这一途径代表了1型糖尿病的胰岛素缺乏或2型糖尿病的胰岛素抵抗与这两种情况下视网膜进行性损害之间的新的潜在联系。在这一应用中，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，我们建议进行一项横断面研究，通过视网膜电描记术来确定糖尿病患者发展为视网膜病变的高危人群，这是我们机构广泛使用的一种非侵入性临床工具。在视网膜病变的早期患者中，我们将测量已被证明与视网膜磷脂高度相关的红细胞磷脂。总之，这些研究旨在建立全身和视网膜磷脂代谢异常与糖尿病视网膜病变早期功能异常之间的新联系。我们将测试相关假设，即视网膜脂肪生成的变化有助于糖尿病视网膜病变，以及外周血中的脂肪变化与糖尿病视网膜的早期ERG变化高度相关。为此，我们将致力于以下三个目标：(1)确定Fas在调节视网膜脂质代谢中的作用；(2)确定靶向缺失Fas是否会加剧糖尿病动物的视网膜病变；(3)通过对受试者外周血进行基于质谱学的分析，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的合作，这项应用有可能揭示与早期糖尿病视网膜病变相关的脂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基于血液的磷脂生物标记物，可以识别出进展风险较高的患者。一种容易记录的早期视网膜病变的血液指标也可能改善获得护理的机会。通过积极的血糖控制预防微血管疾病的普遍智慧必须与与这些措施相关的死亡率增加的担忧相平衡(23，24)。此外，由于目前的治疗方法不能改善许多患者的糖尿病眼病(25)，而且人们越来越担心当前使用的药物(26，27)的安全性，基于脂质的疗法为这一顽固疾病的治疗提供了一种有吸引力的替代方法。