Mechanisms of neurodegeneration in diabetic retinopathy: Role of spermine oxidase

项目摘要 糖尿病视网膜病变（Diabetic Retinopathy，DR）是糖尿病的主要并发症，是导致劳动年龄人群失明的主要原因 成年人在美国。DR的特征是神经变性和微血管异常。电流 DR的治疗方法治疗疾病的晚期，特别是血管病变， 方面的影响.缺乏有效的治疗方法来预防DR的发生或进展是糖尿病患者的主要问题。 视野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， 治疗目标我们的目标是通过确定精胺的具体作用，为DR的治疗做出贡献 氧化酶（SMO）是多胺代谢途径中的重要酶，在介导神经元损伤中起重要作用。 糖尿病视网膜，并证明其作为DR治疗的治疗靶点的潜力。我们的中央 假设糖尿病引起视网膜神经元中SMO的上调，导致多胺增加 氧化和释放丙烯醛。我们的假设预测，各种蛋白质-丙烯醛加合物的形成 导致糖尿病视网膜的氧化损伤，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）表征涉及SMO诱导的神经元损伤的分子机制 在糖尿病视网膜，和3）确定抑制SMO在DR的治疗潜力。我们的预期 结果包括：1）证实了响应于视网膜内神经元的存活和功能的改变， 在DR模型中操纵SMO表达; 2）鉴定SMO诱导的分子变化， 糖尿病视网膜发生神经元损伤;和3）响应于糖尿病视网膜的视网膜结构和功能的保留 实验性DR模型中的SMO抑制。我们的研究将影响糖尿病视网膜病变领域， 糖尿病视网膜神经元功能障碍机制的新的重要信息 因此可以导致开发精确和有效的靶向治疗以延迟或预防视力 DR患者的损失。限制神经元损伤的概念也适用于其他视觉障碍，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， 视网膜中的线粒体功能障碍可以通过提供新的视觉疗法而促进临床实践 全世界的损失目的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。目的2将检验SMO的上调导致多胺氧化增加、丙烯醛氧化增加的假设。 蛋白加合物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阻断剂可保护DR患者视网膜结构和功能。

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.