权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Loss of the retinal glycocalyx in diabetes

糖尿病患者视网膜糖萼的丧失

基本信息

批准号：
9321055
负责人：
NORMAN R HARRIS
金额：
$ 36.25万
依托单位：
LOUISIANA STATE UNIV HSC SHREVEPORT
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9321055
关键词：
Address Adhesions Adult Attenuated Back Binding Blindness Blood Circulation Blood Vessels Blood capillaries CD31 Antigens Cell Adhesion Cell surface Cessation of life Cleaved cell Clinical Development Diabetes Mellitus Diabetic Retinopathy Disease Docking Dropout Emigrations Endothelial Cells Endothelium Enzymes Experimental Models Extracellular Domain Glycocalyx Glycoproteins Glycosaminoglycans Glypican Health Hemorrhage Heparan Sulfate Proteoglycan Heparitin Sulfate Hypoxia Individual Lead Leukocyte Adhesion Molecules Leukocyte-Adhesion Receptors Leukocytes Matrix Metalloproteinases Mechanics Mediating Microaneurysm Microcirculation Microvascular Dysfunction Modeling Nitric Oxide Pathology Permeability Plasma Production Proteoglycan Retina Retinal Role Sampling Signal Transduction Site Surface Testing Thick Thrombosis Tissues Tube Vision angiogenesis capillary cotton wool spots cytokine diabetic heparanase neovascularization prevent receptor retina blood vessel structure shear stress syndecan

项目摘要

Diabetic retinopathy, the leading cause of blindness in adults, is recognized as a microvascular complication of the disease, with retinal microvessels characterized by microaneurysms, leukocyte-endothelial cell adhesion, hemorrhages, increased permeability, capillary occlusion, neovascularization, etc. We propose that an underlying contributor to the retinal pathology is the loss of the endothelial surface layer (glycocalyx). The glycocalyx is a dense layer of molecules including proteoglycans (e.g., syndecan-1) and glycosaminoglycans (GAGs, e.g., heparan sulfate). The glycocalyx facilitates the interactions between plasma molecules and their endothelial receptors, inhibits thrombosis, shields against leukocyte-endothelial cell adhesion, transduces shear force, and acts as a permeability barrier. Inasmuch as heparan sulfate can be cleaved by heparanase, and syndecan-1 has multiple sites on its extracellular domain susceptible to cleavage by matrix metalloproteinases (MMPs), we hypothesize a role for these enzymes in the loss of the glycocalyx in diabetes. With a combined attack on both syndecan-1 and heparan sulfate, the functions of the glycocalyx could be substantially lost, which has been shown in many models to enhance leukocyte-endothelial cell adhesion. Such adhesion is thought to promote the occlusion of capillaries in the diabetic retina, leading to the subsequent development of “acellular” capillaries that are no longer perfused, creating ischemic zones. Ultimately, the resulting hypoxia promotes uncontrolled angiogenesis that interferes with clear vision. When a leukocyte adheres to the endothelial surface, it can eventually be coerced back into the bloodstream by shear forces, or alternatively, cross the endothelium (emigrate) into the surrounding tissue in a mechanism mediated by platelet endothelial cell adhesion molecule-1 (PECAM-1). However, loss of PECAM-1 prevents leukocyte emigration, and adherent leukocytes can be trapped within capillaries causing continued occlusion and eventual capillary death. We and others have noted a loss of PECAM-1 from the diabetic retinal microcirculation, with this loss possibly caused by mechanisms such as MMP-mediated cleavage, cytokine- mediated decrease in production, and/or proteasomal degradation. The following specific aims address the overall hypothesis that diabetes induces the loss of key endothelial surface molecules that results in leukocyte adhesion, capillary occlusion, and eventual development of acellular capillaries: (1) Investigate the hypothesis that the loss of heparan sulfate from the diabetic retinal microcirculation is mediated directly by heparanase and indirectly by MMP-facilitated cleavage of syndecan-1, (2) Determine the mechanism(s) responsible for the loss of PECAM-1 from the diabetic retinal microcirculation, by testing for decreased expression, increased proteasomal degradation, and cleavage from the endothelial cell surface, and (3) Investigate the hypothesis that capillary occlusion by leukocytes and the development of acellular capillaries can be attenuated by protection of the endothelial surface layer.

糖尿病视网膜病变是成人失明的主要原因，被认为是糖尿病的微血管并发症