Study of diabetic retinopathy

糖尿病视网膜病变的研究

基本信息

批准号：
8523858
负责人：
Timothy S Kern
金额：
$ 38.84万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1977
资助国家：
美国
起止时间：
1977-12-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8523858
关键词：
Abbreviations Abnormal Cell Adhesions Adult Age Animals Applications Grants Basophils Binding Blindness Blood Cells Blood Vessels Blood capillaries Bone Marrow Bone Marrow Cells CCL2 gene Cell Adhesion Molecules Cells Cessation of life Chemotactic Factors Chimera organism Cicatrix Data Defect Developed Countries Development Diabetes Mellitus Diabetic Retinopathy Diabetic mouse Emigrations Endothelial Cells Endothelium Functional disorder Genetic Green Fluorescent Proteins Histopathology Hyperglycemia Immune system Inflammation Inflammatory Lesion Leukocytes Light Lymphocyte Marrow Mediating Metabolic Metabolism Microglia Modification Monocyte Chemoattractant Protein-1 Mus Myelogenous Myeloid Cells NADPH Oxidase NADPH Oxidase 1 Neural Retina Neuroglia Neurons Nitric Oxide Synthase Nomenclature Oxidants Pathogenesis Pathology Pathway interactions Play Polymerase Procedures Process Production Protein Isoforms Reactive Oxygen Species Recruitment Activity Research Retina Retinal Retinal Degeneration Retinal Diseases Retinal Hemorrhage Role Staging Stem cells Structure Testing Therapeutic Time Work base capillary cell killing cell type cytokine diabetic patient eosinophil inflammatory marker irradiation killings monocyte neutrophil novel novel strategies prevent public health relevance vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Evidence generated by us and others in animals provides evidence that inflammatory processes contribute to the development of at least the early stages of diabetic retinopathy, and especially the degeneration of retinal capillaries. How this capillary degeneration in diabetes is not clear, but most studies to date have focused on metabolic defects within cells of the retina and its vasculature. The present grant proposal is based on novel observations we have made over the previous several years suggesting that proinflammatory pathways within cells derived from bone marrow are critical in the development of the retinopathy. We have found that the vascular lesions of diabetic retinopathy can be prevented merely by eliminating either iNOS or PARP-1 from the marrow-derived cells only. Which myeloid cells are responsible for development of lesions of diabetic retinopathy, how they cause the diabetes-induced abnormalities in structure and function, and how to inhibit these leukocyte-driven abnormalities are not known, and are the subjects of the proposed research. In this proposal, we will (1) characterize which marrow-derived cell types participate in the development of early stages of diabetic retinopathy, (2) determine the role of chemoattractants in recruitment of marrow-derived cells to the retina in diabetes, and if the chemoattraction is critical to diabetes-induced degeneration of retinal capillaries, and (3) investigate the mechanism(s) by which marrow-derived cells kill retinal cells in diabetes, focusing initially on the role of reactive oxygen species generated by NADPH oxidase in the development of diabetes-induced inflammation. We also will determine if the abnormalities within the marrow-derived cells cause degeneration of neuroglial cells of the retina. We postulate that these diabetes-induced degenerative changes in the retina can be inhibited by blocking the abnormal metabolism within the marrow-derived cells, or by blocking the adhesion between those blood cells and retinal vascular cells. This hypothesis offers a novel approach to inhibiting the retinopathy (cause circulating leukocytes to release a factor that inhibits binding of white blood cells to the endothelium) which we will test in this proposal. This data is novel, and indicates that views of diabetic retinopathy need to expand beyond the traditional retina- or vascular-specific view of pathogenesis to include also bone marrow-derived cells. PUBLIC HEALTH RELEVANCE: Diabetic retinopathy is a leading cause of vision loss in working-age adults in industrialized nations. In addition to abnormalities that disruption of light hitting the retina (fibrovascular scars, hemorrhage, retinal thickening), there are also alterations in function of the neural cells of the retina. There is very little understanding how this pathology develops. Our preliminary studies demonstrate for the first time that white blood cells play a critical role in the early stages of diabetic retinopathy. This proposal explores which white blood cells are responsible for this abnormality, how they are attracted to the retina, and how they kill retinal cells. We also test a possible therapeutic option to stop white blood cells from interacting with endothelial cells as an option to inhibit the retinopathy.

描述（由申请人提供）：我们和其他人在动物身上产生的证据表明，炎症过程至少有助于糖尿病视网膜病变早期阶段的发展，尤其是视网膜毛细血管的变性。糖尿病中的毛细血管变性如何发生尚不清楚，但迄今为止大多数研究都集中在视网膜细胞及其脉管系统内的代谢缺陷。目前的资助提案基于我们在过去几年中所做的新观察，表明骨髓来源的细胞内的促炎途径对于视网膜病变的发展至关重要。我们发现，仅通过从骨髓源性细胞中消除 iNOS 或 PARP-1 即可预防糖尿病性视网膜病的血管病变。哪些骨髓细胞导致糖尿病视网膜病变的发展，它们如何导致糖尿病引起的结构和功能异常，以及如何抑制这些白细胞驱动的异常尚不清楚，并且是拟议研究的主题。在本提案中，我们将（1）描述哪些骨髓源性细胞类型参与糖尿病视网膜病变早期阶段的发展，（2）确定趋化剂在糖尿病视网膜募集骨髓源性细胞中的作用，以及如果化学吸引对于糖尿病引起的视网膜毛细血管变性至关重要，并且（3）研究骨髓源性细胞杀死糖尿病视网膜细胞的机制，首先关注活性氧的作用NADPH 氧化酶在糖尿病引起的炎症发展过程中产生的物种。我们还将确定骨髓源性细胞内的异常是否会导致视网膜神经胶质细胞的变性。我们假设，可以通过阻断骨髓源性细胞内的异常代谢，或通过阻断血细胞与视网膜血管细胞之间的粘附来抑制糖尿病引起的视网膜退行性变化。这一假设提供了一种抑制视网膜病变的新方法（导致循环白细胞释放一种抑制白细胞与内皮细胞结合的因子），我们将在本提案中对其进行测试。这一数据是新颖的，表明糖尿病视网膜病变的观点需要扩展到传统的视网膜或血管特异性发病机制观点之外，还包括骨髓来源的细胞。公共卫生相关性：糖尿病视网膜病变是工业化国家工作年龄成年人视力丧失的主要原因。除了光线照射到视网膜的异常（纤维血管疤痕、出血、视网膜增厚）之外，视网膜神经细胞的功能也发生改变。人们对这种病理如何发展知之甚少。我们的初步研究首次证明白细胞在糖尿病视网膜病变的早期阶段发挥着关键作用。该提案探讨了哪些白细胞导致了这种异常，它们如何被吸引到视网膜，以及它们如何杀死视网膜细胞。我们还测试了一种可能的治疗方案，以阻止白细胞与内皮细胞相互作用，作为抑制视网膜病变的一种选择。