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: 9467549
• 负责人: DANIELLE M. ROBERTSON
• 金额: $ 40.5万
• 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 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9467549
• 关键词: Age; Beta Cell; Biochemical; Biological; Biological Assay; Biological Markers; Blindness; Cell Nucleus; Cell membrane; Clinical Markers; Clinical Research; Complex; Complications of Diabetes Mellitus; Cornea; Corneal Diseases; Data; Diabetes Mellitus; Disease; Early Intervention; Economic Burden; Epidemic; Epithelial; Epithelial Cells; Event; Film; Functional disorder; Gene Expression; Gene Expression Regulation; Goals; Human; Hybrids; Hyperglycemia; Impaired wound healing; Impairment; 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; Neuroepithelial; 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; potential biomarker; prevent; public health relevance; receptor; receptor expression; reflectance confocal microscopy; 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.