Endothelin-1 System Activation and Retinal Microvascular Dysregulation during Early Diabetes

早期糖尿病期间内皮素-1 系统激活和视网膜微血管失调

基本信息

批准号：
10504529
负责人：
TRAVIS W HEIN
金额：
$ 37.88万
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：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10504529
关键词：
Address Adult Age Animal Model Animals Blindness Blood Flow Velocity Blood Vessels Blood flow Clinical Complications of Diabetes Mellitus Data Development Diabetes Mellitus Diabetic Angiopathies Diabetic Retinopathy Disease Electroretinography Endothelin-1 Endothelin-converting enzyme 1 Endothelium Event Eye Eye diseases Family suidae Functional disorder Goals Health Human Inflammatory Insulin-Dependent Diabetes Mellitus Ischemia Knowledge Lead Link MAPK8 gene Microcirculation Microvascular Dysfunction Modeling Molecular Molecular Target Morphology N-terminal Neural Retina Neurons Nutrient Ocular Physiology Outcome Oxygen Pathology Pathway interactions Perfusion Phosphotransferases Physiological Production Proteins ROCK1 gene Regulation Research Retina Retinal Diseases Rho-associated kinase Role Signal Pathway Signal Transduction Signaling Molecule Streptozocin Structure System Testing Time United States Vasoconstrictor Agents Vasomotor Vision aged arteriole base blood damage constriction diabetic differential expression effective therapy experience extracellular improved innovation insight knock-down novel p38 Mitogen Activated Protein Kinase preservation relating to nervous system response retinal damage retinal ischemia sight restoration stress kinase targeted treatment treatment strategy type I diabetic vasoconstriction venule

项目摘要

Diabetes mellitus causes microvascular complications in the retina and is a leading cause of blindness in the United States. Treatments to restore vision are limited. Reduced retinal blood flow occurs in early diabetes, suggesting that vasomotor dysregulation of retinal arterioles and/or venules leading to ischemia may contribute to later retinal damage. However, no study has examined both arteriolar and venular vasomotor function together in the retina of same diabetic subjects. Thus, a gap in knowledge is the limited understanding of mechanisms for retinal arteriolar/venular vasomotor dysregulation in early diabetes to yield treatment before overt pathology. Excessive production of vasoconstrictor and inflammatory agent endothelin-1 (ET-1) in the retina occurs in early diabetes, so in-depth insight into molecular events regulating vasomotor responses to ET-1 in health and disease has clinical implication. This proposal is based on evidence in type 1 diabetic pigs showing reduced retinal blood flow at 2-wk diabetes, along with elevated retinal lactate and diminished oscillatory potentials in the electroretinogram, indicating retinal ischemia and neural abnormality. Also, vitreous ET-1 level and retinal arteriolar endothelin- converting enzyme-1 (ECE-1) activity were elevated in diabetic pigs. Because ET-1 is derived from ECE-1 and causes vasoconstriction via Rho kinase (ROCK) signaling, activation of ECE-1/ROCK may lead to retinal vasomotor dysregulation and flow deficiency in early diabetes. Interestingly, diabetes enhances retinal venular, but not arteriolar, constriction to ET-1 by activating reverse-mode Na+-Ca2+ exchanger (NCX), possibly involving Na+-H+ exchanger-1 (NHE1) and stress kinases (p38 and JNK). Thus, the objective of this study is to unveil the sequential molecular pathways for vasomotor dysregulation of retinal arterioles and venules that promote retinal ischemia in early diabetes. The central hypothesis is that early diabetes activates microvascular ECE-1 leading to enhanced ET- 1 production, which promotes retinal arteriolar constriction via Ca2+-dependent ROCK2/JNK signaling. In early diabetes, the elevated ET-1 not only elicits retinal venular constriction via Ca2+-dependent ROCK1/JNK axis but also augments the response by further promoting Ca2+ entry through activation of the p38/NHE1/NCX axis. The cooperative promotion of arteriolar and venular constrictions to elevated ET-1 contributes to retinal ischemia and neural abnormality. Two specific aims will be pursued to support the hypothesis: (1) Determine roles of ET-1 system activation and its molecular signaling in promoting retinal arteriolar constriction and consequent retinal ischemia via Ca2+-dependent ROCK2/JNK axis in early diabetes. (2) Determine roles of ET-1 system activation and its molecular signaling to augment retinal venular constriction with consequent retinal ischemia via Ca2+- dependent ROCK1/JNK axis and activated p38/NHE1/NCX signaling pathway in early diabetes. Outcomes will advance the knowledge of diabetes-induced retinal complications and suggest effective molecular targets for improving and protecting retinal microvascular perfusion of the retina in early-stage diabetes before development of retinal structure damage.

糖尿病会导致视网膜微血管并发症，是美国失明的主要原因国家。恢复视力的治疗方法有限。早期糖尿病患者视网膜血流量减少，表明导致缺血的视网膜小动脉和/或小静脉的血管舒缩失调可能会导致后来的视网膜病变损害。然而，尚无研究同时检查视网膜中的小动脉和静脉血管舒缩功能。同样的糖尿病受试者。因此，知识上的差距是对视网膜机制的了解有限。早期糖尿病中的小动脉/静脉血管舒缩失调，以便在出现明显病理之前进行治疗。过多的早期糖尿病时，视网膜会产生血管收缩剂和炎症剂内皮素-1 (ET-1)，因此，深入了解健康和疾病中调节 ET-1 血管舒缩反应的分子事件已经临床意义。该提议基于 1 型糖尿病猪的视网膜血流量减少的证据糖尿病两周后，视网膜乳酸升高，视网膜电图振荡电位降低，提示视网膜缺血和神经异常。此外，玻璃体 ET-1 水平和视网膜小动脉内皮素 - 糖尿病猪的转化酶-1 (ECE-1) 活性升高。因为 ET-1 源自 ECE-1 并导致通过 Rho 激酶 (ROCK) 信号传导进行血管收缩，ECE-1/ROCK 的激活可能导致视网膜血管舒缩早期糖尿病的失调和血流不足。有趣的是，糖尿病会增强视网膜小静脉，但不会增强小动脉，通过激活反向模式 Na+-Ca2+ 交换器 (NCX) 收缩 ET-1，可能涉及 Na+-H+ 交换器-1 (NHE1) 和应激激酶（p38 和 JNK）。因此，本研究的目的是揭示序列分子视网膜小动脉和小静脉血管舒缩失调的途径，促进早期视网膜缺血糖尿病。中心假设是早期糖尿病激活微血管 ECE-1 导致 ET-1 增强 1 的产生，通过 Ca2+ 依赖性 ROCK2/JNK 信号传导促进视网膜小动脉收缩。早在糖尿病中，升高的 ET-1 不仅通过 Ca2+ 依赖性 ROCK1/JNK 轴引起视网膜小静脉收缩，而且还通过激活 p38/NHE1/NCX 轴进一步促进 Ca2+ 进入来增强反应。这协同促进小动脉和小静脉收缩导致 ET-1 升高，导致视网膜缺血和神经异常。将追求两个具体目标来支持该假设：（1）确定 ET-1 的作用系统激活及其分子信号传导促进视网膜小动脉收缩和随后的视网膜早期糖尿病中通过 Ca2+ 依赖性 ROCK2/JNK 轴实现缺血。 (2) 确定ET-1系统激活的作用及其分子信号通过 Ca2+- 增强视网膜小静脉收缩，从而导致视网膜缺血早期糖尿病中依赖的 ROCK1/JNK 轴和激活的 p38/NHE1/NCX 信号通路。结果将增进对糖尿病引起的视网膜并发症的认识，并提出有效的分子靶点改善和保护发育前早期糖尿病患者的视网膜微血管灌注视网膜结构损伤。