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

Roles of LOX-1 and Stress-Activated Kinases in Retinal Dysfunction during Early Diabetes

LOX-1 和应激激活激酶在早期糖尿病视网膜功能障碍中的作用

基本信息

批准号：
8888305
负责人：
TRAVIS W HEIN
金额：
$ 46.24万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8888305
关键词：
Address Animal Model Antioxidants Blindness Blood Glucose Blood Vessels Blood flow Cardiovascular Diseases Cells Chronic Clinical Complications of Diabetes Mellitus Data Development Diabetes Mellitus Diabetic Retinopathy Early treatment Electroretinography Endothelium Enzymes Event Eye Family suidae Functional disorder Goals Human Hyperglycemia Impairment Insulin-Dependent Diabetes Mellitus Ischemia LOX gene Lead Lectin Ligands Link Low Density Lipoprotein Receptor MAPK8 gene Mediating Metabolism Microcirculation Modality Modeling Molecular Molecular Target Muscle function N-terminal Neural Retina Neurons Neurophysiology - biologic function Nitric Oxide Nitric Oxide Synthase Nutrient Nutritional Outcome Oxidative Stress Oxygen Pathogenesis Pathology Phosphorylation Phosphotransferases Pilot Projects Production Proteins Regulation Reporting Resistance Retina Retinal Retinal Diseases Role Signal Transduction Signaling Molecule Site Small Interfering RNA Smooth Muscle Staging Streptozocin Stress Superoxides System Technology Testing Therapeutic Time Translating Ubiquitin Up-Regulation Vascular Diseases Vascular blood supply Vasomotor Vision Visual impairment animal model development arteriole diabetic early onset effective therapy endothelial dysfunction human NOS3 protein improved innovation intravitreal injection multicatalytic endopeptidase complex novel oxidized low density lipoprotein public health relevance receptor relating to nervous system retinal damage retinal ischemia targeted treatment

项目摘要

DESCRIPTION (provided by applicant): Retinopathy is a major complication of diabetes mellitus and a leading cause of blindness. Treatment modalities for restoring retinal function are relatively ineffective. Although proper retinal function relies on a sufficient supply of blood flo and alterations of both neural and vascular retina have been reported, the mechanism and temporal relationship between neural retina damage and vasomotor function remains unclear. Therefore, simultaneous assessment and unveiling the mechanism of vascular and neural changes in the retina during early diabetes is vital to our understanding of the retinal pathogenesis as well as to development of new therapies for early treatment. Although oxidative stress is implicated in retinal damage in diabetic retinopathy, clinical therapy with antioxidants has been mostly ineffective, suggesting other mechanisms may be involved in sustaining vasomotor and neural retina dysfunction. Also, development of an animal model of diabetes relevant to the human retinal microcirculation and its pathophysiology is lacking. To address these clinically important issues, we have developed a streptozocin-induced type 1 diabetes model in the pig, an animal model that we have shown to resemble the human in retinal vasomotor regulation and dysregulation. Our preliminary data show that within 2 wk of diabetes, endothelium-dependent nitric oxide (NO)-mediated dilation of retinal arterioles is impaired. Elevation of superoxide within diabetic retinal arterioles was observed but antioxidants did not improve endothelium-dependent dilation. Vasomotor impairment was improved by blockade of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), proteasomes or phosphorylation of c-Jun N- terminal kinase-1 (JNK1). LOX-1 and JNK1 are implicated in cardiovascular diseases possibly by altering endothelial NO synthase activity, but their signaling associated with retinal vascular disease remains unknown. Since scotopic b-wave amplitude is also reduced during 6-wk but not 2-wk diabetes, it appears vasomotor dysfunction precedes inner neural retina damage. Thus, the goal of this study is to delineate the link between LOX-1 and JNK1 in the retinal endothelial dysfunction and to determine whether these two molecules can serve as novel targets for improving retinal arteriolar function, along with secondary amelioration of neural retina function, during early diabetes. We will test the hypothesis that early diabetes initiates superoxide-dependent upregulation of LOX-1 and subsequent downstream JNK1/ubiquitin-proteasome signaling for sustained degradation of SIRT1 in the retinal arteriolar endothelium, which leads to reduction of NO-mediated dilation prior to neural retina dysfunction. We will pursue two specific aims: (1) Determine the contributions of superoxide and LOX-1 to diabetes-induced endothelial dysfunction of retinal arterioles prior to neural retina damage; (2) Delineate the contribution of JNK1-dependent phosphorylation and ubiquitin-proteasome degradation of SIRT1 to diabetes-induced endothelial dysfunction of retinal arterioles. Outcomes from basic findings will be translated to therapeutic treatment of retinal vascular disease via siRNA technology in early diabetes.