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.

项目摘要糖尿病性视网膜病（DR）是糖尿病的主要并发症，是工人失明的主要原因在美国的成年人。 DR的特征是神经退行性和微血管异常。当前的 DR治疗该疾病晚期的治疗疗法，尤其是血管病，并且有不良方面效果。缺乏有效的治疗方法来预防DR的发生率或进展是一个主要问题视觉领域。减少糖尿病患者视力丧失进展的关键障碍是缺乏了解导致糖尿病诱导的神经元损伤的分子机制，这可以使用治疗靶标。我们的目标是通过定义精子的特定作用来为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性视网膜并通过证明其作为DR治疗的治疗靶标的潜力。我们的中心假设是糖尿病在视网膜神经元中引起SMO的上调，导致多胺增加丙烯醛的氧化和释放。我们的假设预测形成了各种蛋白质 - 丙酸加合物在糖尿病性视网膜中引起氧化损伤，导致神经元功能障碍。我们的目标是：1）确定 SMO过表达/下调在介导神经元损伤和功能障碍中的影响 DR的实验模型； 2）表征与SMO诱导的神经元损伤有关的分子机制在糖尿病性视网膜中，3）确定抑制DR中SMO的治疗潜力。我们的期望结果包括1）表现出内部视网膜神经元存活的改变，并响应于在DR模型中操纵SMO表达； 2）鉴定SMO诱导的分子变化神经元损害发生在糖尿病性视网膜中； 3）响应于视网膜结构和功能实验DR模型中的SMO抑制作用。我们的研究将通过提供糖尿病性视网膜病领域有关神经元在糖尿病性视网膜中功能失调的机制的新的和重要的信息因此，可以导致制定准确有效的靶向疗法，以延迟或防止视力 DR患者的损失。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和视网膜中的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损失。 AIM 1将检验以下假设：SMO上调会导致糖尿病的神经元损伤视网膜。 AIM 2将检验以下假设：SMO的上调会导致多胺氧化增加，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。 AIM 3将检验假设 SMO封锁可以保留DR中的视网膜结构和功能。