Effects of systemic disease on corneal epithelial pathophysiology

全身性疾病对角膜上皮病理生理学的影响

• 批准号: 9057553
• 负责人: DANIELLE M. ROBERTSON
• 金额: $ 40.46万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9057553
• 关键词: Age; Biochemical; Biological; Biological Assay; Biological Markers; Blindness; Cell Nucleus; Cell membrane; Clinical Markers; Clinical Research; Complex; Complications of Diabetes Mellitus; Confocal Microscopy; Cornea; Corneal Diseases; Data; Diabetes Mellitus; Disease; Economic Burden; Epidemic; Epithelial; Epithelial Cells; Event; Film; Functional disorder; Gene Expression; Gene Expression Regulation; Goals; Health; Human; Hybrids; Hyperglycemia; Impaired wound healing; In Situ; In Vitro; Inflammation; Inflammation Mediators; Insulin; Insulin Receptor; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Insulin-Like Growth Factor Receptor; Laboratories; Lead; Ligands; Link; Mediating; Mediator of activation protein; Modeling; Morphology; Names; Nerve; Nerve Fibers; Nerve Plexus; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Ocular Pathology; Oxidative Stress; Pain; Pathology; Pathway interactions; Patient risk; Patients; Physiology; Prevalence; Proteins; Refractory; Regulation; Retinal; Retinal Diseases; Risk; Role; Somatomedins; Systemic disease; Testing; United States; Vision; burden of illness; corneal epithelium; diabetic; glycemic control; glycogen synthase kinase 3 beta; human tissue; in vivo; insulin sensitivity; insulin signaling; novel; originality; potential biomarker; prevent; receptor; receptor expression; restoration; stem

 DESCRIPTION (provided by applicant): Ocular complications from diabetes are a leading cause of blindness in the United States. Throughout the next few decades, the prevalence of complications stemming from Type 2 Diabetes Mellitus (T2DM) is expected to rise, increasing the economic burden of the disease. The goals of this proposal are: (1) to define the pathophysiological mechanisms that result in painful and often refractory diabetic corneal disease and; (2) to identify biomarkers for use in detecting at-risk patients prior to the onset of sight threatening ocular disease. This proposal will test three novel hypotheses: (1) That IGF-1 and insulin mediate distinct events at the plasma membrane and in the nucleus through regulation of Hybrid-R, IGF-1R and INSR. (2) That increasing levels of inflammation and oxidative stress, and a loss of trophic support from corneal nerves, results in aberrant Hybrid-R expression and function. (3) That, in addition to regulating Hybrid-R, changes in the amount of IGF-related proteins in tears represent potential biomarkers to identify patients at-risk for significant ocular pathology in T2DM. We will test these hypotheses in the following three aims: Aim 1: (A) Evaluate specific factors that control Hybrid-R formation, insulin sensitivity and GSK3 beta activity in corneal epithelial cells. (B) Identify nuclear targets for Hybrid-R, IGF-1R, and INSR. Aim 2: (A) Test the effects of IGF-1, IGF-II, insulin, and IGFBP3 on corneal epithelial cells and nerve fiber loss in the presence of inflammatory mediators and hyperglycemia-induced oxidative stress. (B) Characterize the effects of T2DM on Hybrid-R mediated gene regulation and correlate with diabetes-related changes in the corneal subbasal nerve plexus and terminal epithelial nerves in situ. Aim 3: Determine whether tear levels of IGF-1, insulin and IGFBP3 in human patients with T2DM correlate with corneal and retinal pathology, using new quantitative microvolume biochemical assays, in vivo confocal microscopy (IVCM), and clinical markers of corneal and retinal disease. These aims will be accomplished using a combination of in vitro culture models, in situ human tissue analysis, and in vivo clinical studies to investigate how the pathophysiological effects from T2DM impacts the morphology of corneal nerves, the physiology of the tear film, and the corneal epithelium. These will be the first studies to investigate a rolefor the Hybrid-R in mediating corneal disease in diabetes. These studies also propose a novel biological mechanism for impaired local insulin signaling in corneal disease. Other laboratories are focused on impaired wound healing in diabetes. Our focus is on identifying key mechanisms that contribute to corneal damage; and characterizing and validating tear-film derived biomarkers that will allow for early, interventional approaches to prevent diabetes-related vision loss.

 描述（由申请人提供）：糖尿病引起的眼部并发症是美国失明的主要原因。在接下来的几十年中，2 型糖尿病 (T2DM) 引起的并发症的患病率预计将上升，从而增加该疾病的经济负担。该提案的目标是：（1）确定导致疼痛且通常难治的糖尿病性角膜疾病的病理生理学机制； (2) 确定生物标志物，用于在疾病发作前检测高危患者 威胁视力的眼部疾病。该提案将测试三个新假设：(1) IGF-1 和胰岛素通过调节 Hybrid-R、IGF-1R 和 INSR 介导质膜和细胞核中的不同事件。 (2) 炎症和氧化应激水平的增加以及角膜神经营养支持的丧失，导致 Hybrid-R 表达和功能异常。 (3) 除了调节 Hybrid-R 之外，泪液中 IGF 相关蛋白含量的变化代表了潜在的生物标志物，可用于识别 T2DM 中存在明显眼部病理风险的患者。我们将在以下三个目标中测试这些假设： 目标 1：(A) 评估控制角膜上皮细胞中 Hybrid-R 形成、胰岛素敏感性和 GSK3 β 活性的特定因素。 (B) 确定 Hybrid-R、IGF-1R 和 INSR 的核靶点。目标2：（A）测试IGF-1、IGF-II、胰岛素和IGFBP3对角膜上皮细胞的影响 以及在炎症介质和高血糖诱导的氧化应激存在下神经纤维损失。 (B) 表征 T2DM 对 Hybrid-R 介导的基因调控的影响，并与糖尿病相关的角膜基底神经丛和原位终末上皮神经变化相关。目标 3：利用新的定量微量生化检测、体内共聚焦显微镜 (IVCM) 以及角膜和视网膜疾病的临床标志物，确定 T2DM 患者的泪液 IGF-1、胰岛素和 IGFBP3 水平是否与角膜和视网膜病理相关。这些目标将通过结合体外培养模型、原位人体组织分析和体内临床研究来实现，以研究 T2DM 的病理生理学效应如何影响角膜神经的形态、泪膜和角膜上皮的生理学。这些将是第一个调查 Hybrid-R 在调节糖尿病角膜疾病中的作用的研究。这些研究还提出了角膜疾病中局部胰岛素信号受损的新生物学机制。其他实验室则专注于糖尿病引起的伤口愈合受损。我们的重点是确定导致角膜损伤的关键机制；表征和验证泪膜衍生的生物标志物，这将允许早期干预方法来预防与糖尿病相关的视力丧失。