Regulation of retinopathies

视网膜病变的调节

基本信息

批准号：
8461196
负责人：
CARLOS S SUBAUSTE
金额：
$ 32.22万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8461196
关键词：
Animal Model Automobile Driving Biological Assay Blindness Blood Platelets Blood Vessels Blood capillaries Bone Marrow Transplantation Brain CCL2 gene CD40 Ligand Cause of Death Cell Adhesion Molecules Cell Death Cells Cessation of life Collaborations Degenerative Disorder Development Diabetes Mellitus Diabetic Retinopathy Diabetic mouse Disease Endothelial Cells Event Exhibits Gene Transfer Inflammation Inflammatory Inflammatory Response Injury Intercellular adhesion molecule 1 Ischemia Knock-in Mouse Knockout Mice Laboratories Lead Leukostasis Link Mediating Methodology Microglia Modeling Muller&apos s cell Mus NOS2A gene Neuroglia Neuronal Injury Neurons Nitric Oxide Synthase PTGS2 gene Pathogenesis Pathway interactions Patients Peptides Pericytes Plasma Prostaglandin-Endoperoxide Synthase Regimen Regulation Reperfusion Therapy Research Research Personnel Resistance Retina Retinal Retinal Diseases Retinal Ganglion Cells Role Signal Transduction Signaling Protein T-Lymphocyte TNF Receptor-Associated Factors TNF gene TNFRSF5 gene TNFSF5 gene Testing Therapeutic Tissues Transgenic Mice Treatment Protocols Tumor Necrosis Factor Receptor United States Up-Regulation Vascular Endothelial Growth Factors Wild Type Mouse Work capillary chemokine cytokine diabetic ganglion cell in vivo macroglia member neuron loss novel strategies prevent public health relevance receptor relating to nervous system response retinal neuron single molecule ward

项目摘要

DESCRIPTION (provided by applicant): Diabetic retinopathy is a major cause of blindness in the United States. Upregulation of adhesion molecules, chemokines, nitric oxide synthase (NOS2), inducible cyclooxygenase (COX-2) and vascular endothelial growth factor (VEGF) are pro- inflammatory responses believed to be important in this disease. It is increasingly recognized that these responses contribute to retinal injury and neuro-vascular degeneration. Understanding the regulation of these responses is important because neuronal death largely contributes to visual loss in diabetic retinopathy and currently available treatment regimens have not been able to prevent neuronal loss. The objective of this application is to further our understanding of the regulation of pro-inflammatory responses and neuro-vascular degeneration in diabetic retinopathy. The central hypothesis for the proposed research is that there is a previously unrecognized upstream molecule that triggers the pro-inflammatory responses mentioned above and mediates neuro-vascular degeneration in diabetic retinopathy. Finding that a single molecule controls various cellular responses involved in the pathogenesis of this disease would be significant because it would suggest that targeting a single molecule would impair multiple pro-retinopathy factors. In the first specific aim we will characterize the regulation of pro-inflammatory responses in retinal microglia, Muller cells and endothelial cells. This will be accomplished using immunological assays and gene transfer approaches that block specific signaling proteins. In addition, we will test whether a novel approach to deliver molecules intra-cellularly can be used to block signaling that controls pro-inflammatory responses in retinal cells. Using similar methodologies, in the second specific aim we will characterize the regulation of neuronal and endothelial cell death caused by these pro-retinopathy responses. Using an animal model of diabetic retinopathy in wild-type and knock-out mice we will evaluate the in vivo effects of regulation of inflammation on the development of diabetic retinopathy. The proposed work may lead to new strategies to treat diabetic retinopathy.

描述（由申请人提供）：糖尿病性视网膜病是美国失明的主要原因。粘附分子，趋化因子，一氧化氮合酶（NOS2），诱导型环氧合酶（COX-2）和血管内皮生长因子（VEGF）的上调是炎症反应，被认为对这种疾病很重要。越来越多地认识到，这些反应会导致视网膜损伤和神经血管变性。了解这些反应的调节很重要，因为神经元死亡很大程度上导致糖尿病性视网膜病的视觉丧失，目前可用的治疗方案无法预防神经元丧失。该应用的目的是进一步了解糖尿病性视网膜病中促炎反应和神经血管变性的调节。提出的研究的中心假设是，先前未识别的上游分子触发了上述促炎反应并介导糖尿病性视网膜病中的神经血管变性。发现单个分子控制该疾病发病机理中涉及的各种细胞反应将是重要的，因为它表明靶向单个分子会损害多种促癌症。在第一个特定目的中，我们将表征视网膜小胶质细胞，毛毛细胞和内皮细胞中促炎反应的调节。这将使用阻断特定信号蛋白的免疫学测定和基因转移方法来完成。此外，我们还将测试一种新型的细胞内分子的方法，可用于阻止控制视网膜细胞中促炎反应的信号传导。使用类似的方法，在第二个特定目的中，我们将表征由这些促肿瘤病的反应引起的神经元和内皮细胞死亡的调节。使用野生型和敲除小鼠中糖尿病性视网膜病的动物模型，我们将评估炎症调节对糖尿病性视网膜病发展的体内影响。拟议的工作可能会导致治疗糖尿病性视网膜病的新策略。