Detecting Early Stage Diabetic Retinopathy

描述(由申请人提供)： 糖尿病视网膜病变(DR)是导致20至74岁成年人失明的主要原因。在临床发现之前发现早期视网膜病变将极大地影响DR的管理和治疗。这项提议的目标是开发新的测试，可以作为早期DR的筛查或诊断工具。我们已经确定了几种测试，这些测试显示了在糖尿病引起的具有临床意义的血管病变发生之前的功能障碍变化。这些测试需要进一步评估，以确定1)这些视网膜神经元的功能变化与导致视力丧失的晚期血管病变之间的关系；2)视网膜血管和神经元变化的时间进展，以确定视力丧失测试的可预测性；3)这些测试在确定正常视网膜的同时积极检测视网膜病变的敏感性和特异性；4)如果早期DR的发现提供了一个更早的干预窗口。这项研究设计还提供了一个独特的机会来确定早期DR的病理生理机制。在这项建议中，我们将追求以下目标：目标1：确定非侵入性客观指标来诊断临床前DR，我们将确定早期DR中是否同时出现活性氧簇(ROS)和视网膜和视觉功能障碍，以及这是否与晚期周细胞丢失和无细胞毛细血管相关。将使用接收器工作特性(ROC)分析来确定每项测试的检测阈值。目的：通过评价氧化应激和神经血管功能障碍的时程变化，阐明早期糖尿病视网膜病变的发病机制。为了探讨早期DR的潜在机制，我们将使用功能数据和精心选择的体外标记物来确定DR早期的血管变化是否会导致缺氧，从而导致神经元的变化，或者早期的神经元变化是否会产生炎症反应，从而启动血管功能障碍。目的3.确定早期治疗糖尿病视网膜病变是否能阻止DR的进展。我们将研究三种治疗方法：普通抗氧化剂(AREDS抗氧化剂补充剂)、双效抗氧化剂/抗凋亡剂(牛磺熊去氧胆酸)和胰岛素。每种方法都将在我们的非侵入性检测工具检测到的最早的神经元功能障碍开始时应用，或者在周细胞脱落和荧光素泄漏指示的临床视网膜病变开始时应用。这一目标将决定早期干预是否能防止晚期血管改变。这项建议将建立早期DR的检测工具，并确定早期干预预防疾病进展的效果。这些研究使用I型和II型糖尿病的啮齿动物模型来建立临床上无法接触到的实用和潜在的机械联系。我们通过将临床上可用的设备(ERG、SLO、视网膜摄影)与新的刺激、条件或造影剂相结合，制作了检测工具，以促进快速临床转换。在临床表现和视力丧失之前发现早期SAGE视网膜病变将极大地改善DR的管理和治疗。这些研究的结果将建立一套检测早期DR的客观指标，并将在未来的研究中在人类受试者中进行测试。

DESCRIPTION (provided by applicant): Diabetic retinopathy (DR) is the leading cause of blindness in adults 20 to 74 years of age. Detecting early stage retinopathy prior to the onset of clinical findings would greatly impact the management and treatment of DR. The goal of this proposal is to develop new tests that could serve as screening or diagnostic tools for early DR. We have identified several tests that show dysfunctional changes prior to the onset of clinically-significant vascular lesions induced by diabetes. These tests need to be further evaluated to establish 1) the relationship between theses functional changes in retinal neurons and late stage vascular lesions that cause vision loss; 2) the temporal progression of the retinal vascular and neuronal changes to determine predictability of the test for vision loss; 3) the sensitivity and specificity of the tests to posiively detect retinopathy while identifying normal retinas and 4) if identification of early stage DR provides an earlier window for intervention. The study design also provides a unique opportunity to determine the pathophysiological mechanisms underlying early stage DR. In this proposal, we will pursue the following aims: Aim 1: Identify non-invasive objective measures to diagnose preclinical DR. We will determine if the appearance of reactive oxygen species (ROS) occurs simultaneously with retinal and visual dysfunction in early stage DR and if this correlates with late stage pericyte dropout and acellular capillaries. Receiver operating characteristic (ROC) analysis will be used to determine detection threshold for each test. Aim 2: Elucidate the mechanisms underlying early stage DR by evaluation the timecourse of oxidative stress and neuronal and vascular dysfunction. To investigate the underlying mechanisms of early DR, we will use functional data and carefully chosen ex vivo markers to determine if early-stage vascular changes in DR induce hypoxia which leads to neuronal changes or if early-stage neuronal changes produce an inflammatory response which initiates vascular dysfunction. Aim 3. Determine if treating early stage diabetic retinopathy prevents the progression of DR. We will investigate three therapeutic approaches: a general anti-oxidant (AREDS anti-oxidant supplement), a dual acting anti-oxidant/anti-apoptotic agent (tauroursodeoxycholic acid (TUDCA)) and insulin. Each approach will be applied either at the onset of the earliest neuronal dysfunction as detected by our non-invasive detection tools or at clinical onset of retinopathy as indicated by pericyte dropout and fluorescein leakage. This aim will determine if early intervention prevents late stage vascular changes. This proposal will establish detection tools of early DR and determine the efficacy of early intervention to prevent disease progression. These studies use rodent models of both Type I and Type II diabetes to establish utility and potential mechanistic connections that are clinically inaccessible. We have crafted detection tools by combining clinically available devices (ERG, SLO, retinal photography) with novel stimuli, conditions, or contrast agents to facilitate rapid clinical translation. Detecting early sage retinopathy prior to the onset of clinical findings and vision loss would greatly improve the management and treatment of DR. The results of these studies will establish a set of objective measures for detection of early stage DR that will be tested in human subjects in future studies.