Mechanisms of neurodegeneration in diabetic retinopathy: Role of spermine oxidase

糖尿病视网膜病变的神经变性机制：精胺氧化酶的作用

基本信息

批准号：
9922598
负责人：
Priya Narayanan
金额：
$ 36.61万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9922598
关键词：
Acrolein Adult Adverse effects Antioxidants Blindness Complications of Diabetes Mellitus Defect Dependovirus Development Diabetes Mellitus Diabetic Retinopathy Diabetic mouse Disease Down-Regulation Electroretinography Enzymes Experimental Models Functional disorder Genetic Glaucoma Goals Histologic Human In Vitro Incidence Lead Measures Mediating Metabolic Pathway Mission Modeling Molecular Nerve Degeneration Neuronal Dysfunction Neuronal Injury Neurons Optical Coherence Tomography Outcome Patients Polyamines Post-Translational Protein Processing Prevention Proteins Public Health Research Research Personnel Retina Retinal Role Specimen Structure Synapses Testing Therapeutic Thinness Transgenic Mice United States United States National Institutes of Health Up-Regulation Vascular Diseases Vision Vision Disorders Vision research Visual impairment adduct aged clinical practice density diabetic diabetic patient effective therapy in vivo knock-down mitochondrial dysfunction neuronal survival novel therapeutics optic nerve disorder overexpression oxidation oxidative damage polyamine oxidase preservation prevent response retinal neuron side effect small hairpin RNA targeted treatment therapeutic target treatment effect

项目摘要

PROJECT SUMMARY Diabetic Retinopathy (DR), a major complication of diabetes, is the leading cause of blindness in working-aged adults in the United States. DR is characterized by neurodegeneration and microvascular abnormalities. Current therapies for DR treat advanced stages of the disease, particularly the vasculopathy and have adverse side effects. Lack of effective treatments to prevent the incidence or progression of DR is a major problem in the vision field. A critical barrier to the progress in reducing vision loss in diabetic patients is the lack of understanding of the molecular mechanisms that lead to diabetes-induced neuronal damage which could serve therapeutic targets. Our goal is to contribute to the treatment of DR, by defining the specific role of Spermine Oxidase (SMO, an important enzyme in polyamine metabolic pathway), in mediating neuronal damage in the diabetic retina and by demonstrating its potential as a therapeutic target for DR treatment. Our central hypothesis is that diabetes causes upregulation of SMO in retinal neurons, resulting in increased polyamine oxidation and release of acrolein. Our hypothesis predicts that formation of various protein-acrolein adducts causes oxidative damage in diabetic retina, leading to neuronal dysfunction. Our objectives are: 1) determine the impact of SMO overexpression/downregulation in mediating neuronal damage and dysfunction in experimental model of DR; 2) characterize molecular mechanisms involved in SMO-induced neuronal damage in the diabetic retina, and 3) determine the therapeutic potential of inhibiting SMO in DR. Our expected outcomes include 1) demonstration of alterations in inner retinal neuronal survival and function in response to manipulation of SMO expression in DR models; 2) identification of SMO induced molecular changes by which neuronal damage occurs in diabetic retina; and 3) preservation of retinal structure and function in response to SMO inhibition in experimental DR model. Our studies will impact the field of diabetic retinopathy by providing new and significant information on mechanisms by which neurons become dysfunctional in the diabetic retina and thus can lead to the development of accurate and efficacious targeted therapies to delay or prevent vision loss in DR patients. The concept of limiting neuronal injury is also applicable to other vision disorders such as glaucoma and optic neuropathy. Modulating SMO function to reduce oxidative modifications of proteins and mitochondrial dysfunction in the retina can facilitate towards clinical practice by providing new therapies for vision loss worldwide. Aim 1 will test the hypothesis that upregulation of SMO causes neuronal injury in the diabetic retina. Aim 2 will test the hypothesis that upregulation of SMO causes increased polyamine oxidation, acrolein- protein adducts formation, and mitochondrial dysfunction in the diabetic retina. Aim 3 will test the hypothesis that SMO blockade can preserve retinal structure and function in DR.

项目概要糖尿病视网膜病变（DR）是糖尿病的主要并发症，是导致工作年龄组失明的主要原因在美国的成年人。 DR 的特点是神经变性和微血管异常。当前的 DR 疗法治疗疾病晚期，特别是血管病变，但有副作用影响。缺乏有效的治疗方法来预防 DR 的发生或进展是当今世界的一个主要问题视野。在减少糖尿病患者视力丧失方面取得进展的一个关键障碍是缺乏了解导致糖尿病引起的神经元损伤的分子机制，这可能有助于治疗目标。我们的目标是通过明确 Spermine 的具体作用，为 DR 的治疗做出贡献氧化酶（SMO，多胺代谢途径中的重要酶），介导神经元损伤糖尿病视网膜并证明其作为 DR 治疗靶点的潜力。我们的中央假设是糖尿病导致视网膜神经元中 SMO 上调，导致多胺增加氧化并释放丙烯醛。我们的假设预测各种蛋白质-丙烯醛加合物的形成导致糖尿病视网膜氧化损伤，导致神经元功能障碍。我们的目标是：1）确定 SMO过表达/下调对介导神经元损伤和功能障碍的影响 DR实验模型； 2）表征SMO诱导的神经元损伤的分子机制糖尿病视网膜，3) 确定抑制 SMO 在 DR 中的治疗潜力。我们的预期结果包括 1) 证明视网膜内神经元存活和功能的改变 DR 模型中 SMO 表达的操纵； 2) 识别 SMO 诱导的分子变化糖尿病视网膜发生神经元损伤； 3) 视网膜结构和功能的保存实验 DR 模型中的 SMO 抑制。我们的研究将通过提供影响糖尿病视网膜病变领域关于糖尿病视网膜神经元功能障碍的机制的新的重要信息从而可以开发出准确有效的靶向疗法来延迟或预防视力 DR 患者的流失。限制神经元损伤的概念也适用于其他视力障碍，例如青光眼和视神经病变。调节 SMO 功能以减少蛋白质的氧化修饰视网膜线粒体功能障碍可以通过提供新的视力疗法来促进临床实践全球范围内的损失。目标 1 将检验 SMO 上调导致糖尿病患者神经元损伤的假设视网膜。目标 2 将检验以下假设：SMO 的上调会导致多胺氧化、丙烯醛- 蛋白质加合物的形成和糖尿病视网膜中的线粒体功能障碍。目标 3 将检验假设 SMO 阻断可以保留 DR 中的视网膜结构和功能。