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：
9330861
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 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9330861
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 Lipoprotein Receptor MAPK8 gene Mediating Metabolism Microcirculation Modality Modeling Molecular Molecular Target Muscle function N-terminal NOS3 gene 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 SIRT1 gene Signal Transduction Signaling Molecule Site Small Interfering RNA Smooth Muscle 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 improved innovation intravitreal injection knock-down multicatalytic endopeptidase complex novel novel therapeutics 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.

描述（由适用提供）：视网膜病是糖尿病的主要并发症，是失明的主要原因。恢复视网膜功能的治疗方式相对无效。尽管已经报道了适当的残留功能依赖足够的血流供应以及神经元和血管视网膜的改变，但神经元视网膜损伤与血管舒缩功能之间的机制和临时关系尚不清楚。因此，简单的评估并揭示了早期糖尿病期间视网膜血管和神经元变化的机制对于我们对视网膜发病机理以及用于早期治疗的新疗法的发展至关重要。尽管在糖尿病性视网膜病变的视网膜损伤中隐含氧化应激，但抗氧化剂的临床治疗主要是无效的，这表明其他机制可能与血管舒缩和神经元视网膜功能障碍有关。同样，缺乏与人类残留微循环有关的糖尿病动物模型及其病理生理学。为了解决这些临床上重要的问题，我们在猪中开发了一种链霉菌蛋白诱导的1型糖尿病模型，这是一种动物模型，我们已证明在残留的血管舒张症调控和失调中与人类相似。我们的初步数据表明，在2周的糖尿病中，内皮依赖性一氧化氮（NO）介导的视网膜artiolus介导的字典受到了损害。观察到糖尿病残留artiolus中超氧化物的升高，但抗氧化剂并不能改善内皮依赖性词典。通过阻断氧化氧化物低密度脂蛋白受体-1（LOX-1），蛋白酶体或C-Jun N-末端激酶1（JNK1）的磷酸化（JNK1）的封锁，可以改善血管舒张症。 LOX-1和JNK1通过改变内皮NO合酶活性而与心血管疾病有关，但它们与残留血管疾病相关的信号仍然未知。由于在6周期间，但2周糖尿病期间也降低了SCOTOPIC B波放大器，因此血管舒缩功能障碍似乎是内部神经素损伤的损害。这是这项研究的目的是描述视网膜内皮功能障碍中LOX-1和JNK1之间的联系，并确定这两个分子是否可以作为改善视网膜动脉功能的新目标，以及次生改善我们将检验以下假设：早期糖尿病会启动LOX-1的超氧化物依赖性更新，随后下游JNK1/ubiquitin prototeasomememememememome信号传导，以在视网膜小动脉内皮中持续降解SIRT1，从而导致Neuronal neuronal retina eNuronAl veninal neuronArcountuts降低无介导的内皮。我们将追求两个具体的目的：（1）确定在神经素损伤之前，超氧化物和LOX-1对残留小动脉的内皮功能障碍的贡献；（2）描述了JNK1依赖性的磷酸化和泛素 - 蛋白 - 蛋白酶体降解对残留动脉的糖尿病诱导的内皮功能障碍的贡献。基本发现的结果将通过早期糖尿病中的siRNA技术转化为残留血管疾病的治疗治疗。