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

Vasomotor Dysfunction of Retinal Arterioles in Diabetes

糖尿病视网膜小动脉血管舒缩功能障碍

基本信息

批准号：
9020236
负责人：
TRAVIS W HEIN
金额：
$ 37.81万
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：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9020236
关键词：
Acute Address Adult American Animal Model Antioxidants Biological Availability Blindness Blood Blood Glucose Blood Vessels Blood flow Cardiac health Cardiomyopathies Clinical Complications of Diabetes Mellitus Coronary Data Development Diabetes Mellitus Diabetic Retinopathy Endothelium Enzymes Evaluation Event Eye Eye diseases Family suidae Functional disorder Future Goals Health Heart Heart failure Heterogeneity Hour Human Hyperglycemia Insulin-Dependent Diabetes Mellitus Link MAPK14 gene MAPK8 gene MAPK9 gene Mediating Microcirculation Modeling Molecular Molecular Target Muscle function N-terminal NAD+ kinase Nitric Oxide Nutrient Nutritional Organ Outcome Oxidases Oxidative Stress Oxygen Pathology Peptide Signal Sequences Phosphorylation Phosphotransferases Production Protein Isoforms Proteins ROCK1 gene Regulation Resistance Retina Retinal Retinal Diseases Rho-associated kinase Role Signal Pathway Signal Transduction Site Smooth Muscle Staging Streptozocin Superoxides Testing Vasodilator Agents Vasomotor Vision Visual impairment Xanthine Oxidase animal model development arginase arteriole constriction diabetes control diabetic cardiomyopathy early onset endothelial dysfunction insight multicatalytic endopeptidase complex non-invasive imaging novel novel therapeutics prevent retinal damage

项目摘要

DESCRIPTION (provided by applicant): Retinopathy is a major complication of diabetes mellitus and a leading cause of blindness in American adults. Hyperglycemia is associated with reduced retinal blood flow in early diabetes, suggesting that dysfunction of arterioles may contribute to retinal damage. Interestingly, noninvasive imaging of retinal blood flow is being regarded as providing a "window" into the health of the heart. Although diabetes can impair coronary blood flow and promote cardiomyopathy, it is possible that underlying mechanisms, which remain unclear, contributing to coronary and retinal arteriolar dysfunction are different. Also, development of a diabetes animal model relevant to human microcirculation for mechanistic study of vasomotor dysfunction of arterioles from the retina and heart is lacking. To address these clinically important issues, we developed streptozocin-induced type 1 diabetes in the pig, an animal model that we have shown resembles human in retinal vasomotor regulation/dysregulation. Our preliminary data show that within 2 wk of diabetes, endothelium-dependent nitric oxide (NO)-mediated dilation of retinal and coronary arterioles is specifically impaired. Endothelial dysfunction correlates with oxidative stress and enhanced Rho kinase (ROCK) expression, and can be prevented and restored in coronary arterioles but only prevented in retinal arterioles by antioxidants and arginase blockade. It appears that signaling events leading to their vasomotor dysfunction in short-term diabetes are different. Mechanistic differences in vasodilator dysfunction under acute (3 hr) vs. prolonged (2 to 12 wk) hyperglycemia suggest that temporal control of arginase II and SIRT1, two regulatory enzymes for NO bioavailability, may mediate this pathophysiology in retinal arterioles, whereas continuous activation of c-Jun N-terminal kinase (JNK) and arginase I contributes to coronary dysfunction. However, the exact role and signaling sequence for specific ROCK isoform activation linking to oxidative stress and arginase have not been defined. Herein, we will test the hypothesis that early diabetes activates endothelial ROCK-dependent JNK-interacting protein-1 (JIP1)/JNK signaling, which enhances downstream NAD(P)H oxidase and p38-dependent proteasome activities in retinal arterioles and xanthine oxidase activity in coronary arterioles. Oxidative stress leads to temporal control of arginase II and SIRT1 with subsequent reduction of NO-mediated dilation in retinal arterioles, whereas prolonged elevation of arginase I sustains coronary dysfunction. We will pursue 3 specific aims: (1) Determine whether enhanced ROCK-dependent phosphorylation of JIP1 contributes to diabetes-induced dysfunction of retinal and coronary arterioles by increasing oxidative stress. (2) Determine whether enhanced JNK-dependent oxidase signaling contributes to diabetes-induced dysfunction of retinal and coronary arterioles. (3) Determine whether enhanced arginase activity and p38-induced activation of proteasomes contribute to temporal control of diabetes-induced dysfunction of retinal and coronary arterioles. Outcomes will identify novel targets involved in retinal and coronary arteriolar dysfunction during early diabetes.

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Newly Identified Peptide, Peptide Lv, Promotes Pathological Angiogenesis.

新鉴定的肽 Lv 可促进病理性血管生成。

DOI：
10.1161/jaha.119.013673
发表时间：
2019
期刊：
Journal of the American Heart Association
影响因子：
5.4
作者：
Shi,Liheng;Zhao,Min;Abbey,ColetteA;Tsai,Shu-Huai;Xie,Wankun;Pham,Dylan;Chapman,Samantha;Bayless,KaylaJ;Hein,TravisW;RosaJr,RobertH;Ko,MichaelL;Kuo,Lih;Ko,GladysY-P
通讯作者：
Ko,GladysY-P

Constriction of Retinal Venules to Endothelin-1: Obligatory Roles of ETA Receptors, Extracellular Calcium Entry, and Rho Kinase.