Role and Regulation of Nox4 in the retina during diabetes

Nox4在糖尿病期间视网膜中的作用和调节

• 批准号: 407606212
• 负责人: Dr. Anne Rübsam
• 金额: --
• 依托单位: Klinik für Augenheilkunde (CVK)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/407606212?language=en
• 关键词: Role; Regulation; Nox4; retina; during

The prevalence of type 2 diabetes is increasing at an alarming rate with approximately 93 million people affected worldwide and 28 million of them having vision-threatening diabetic retinopathy (DR), the major ocular complication of diabetes. Therapies utilizing antibodies against the growth factor Vascular endothelial growth factor (VEGF) have tremendously improved the treatment of proliferative diabetic retinopathy and macular edema, the two late stages of DR, but there are still no therapies targeting early stages of the disease to prevent alterations of the neural retina and thereby preserve visual function. Several reviews have summarized that retinal dysfunction associated with diabetes may be viewed as a change in the retinal neurovascular unit. The neurovascular unit refers to the physiological and biochemical relationship among blood-vessel endothelial cells and pericytes, astrocytes, Müller glial cells, and neurons which are intimately associated to influence the blood– retina barrier. Therefore, new therapeutic approaches that address vascular dysfunction and neural degeneration are required. Hyperglycemia-dependent generation of reactive metabolites are known to cause excessive reactive oxygen species (ROS) production, which are likely to be a key contributor to the development of DR. NADPH (nicotinamide adenine dinucleotide phosphate) enzymes generate ROS and they are known to be widely distributed throughout the retina. Nox 4, one of the 7 isoforms of the Nox family, has been implicated in numerous pathways such as signal transduction, cell differentiation and death. Evidence that Nox4 is an important source of ROS in the retina during DR was provided by a study demonstrating that depletion of Nox4 significantly decreased ROS production, VEGF expression and reduced vascular permeability in diabetic rodents. To date most studies on the role of Nox4 in the retina utilized retinal or other organ derived endothelial cells, which contribute to the vascular changes associated with DR. Still today, there is a gap of knowledge regarding the role and regulation of Nox4 in the retina outside of the vasculature, celltypes which are particularly susceptible to metabolic changes and contribute to the early pathophysiological changes in DR. Thus, I aim to develop a complete picture of Nox4 activity in the retina during diabetes by evaluating the role and regulation of Nox4 as major source of ROS in the retinal neurons, Müller cells and pericytes under diabetic conditions in culture and in two rodent models of diabetes (type 1 & 2). I further want to evaluate the rationale of Nox4 inhibition in preventing oxidative stress induced early neurodegenerative changes in DR. If such a treatment could be realized, it may be possible to promote retinal cell survival in DR at the earliest stages of its development.

2型糖尿病的患病率正在以惊人的速度增加，全球约有9300万人受到影响，其中2800万人患有威胁视力的糖尿病视网膜病变（DR），这是糖尿病的主要眼部并发症。利用针对生长因子血管内皮生长因子（VEGF）的抗体的疗法已经极大地改善了增殖性糖尿病视网膜病变和黄斑水肿（DR的两个晚期阶段）的治疗，但是仍然没有针对疾病的早期阶段的疗法来防止神经视网膜的改变，从而保护视觉功能。一些综述总结了糖尿病相关的视网膜功能障碍可被视为视网膜神经血管单位的变化。神经血管单位是指血管内皮细胞与周细胞、星形胶质细胞、Müller神经胶质细胞和神经元之间的生理和生化关系，它们密切相关以影响血-视网膜屏障。因此，需要解决血管功能障碍和神经变性的新治疗方法。已知反应性代谢物的高血糖依赖性产生会导致过量的活性氧（ROS）产生，这可能是DR发展的关键因素。NADPH（烟酰胺腺嘌呤二核苷酸磷酸）酶产生ROS，并且已知它们广泛分布在整个视网膜中。Nox 4是Nox家族的7种亚型之一，参与信号转导、细胞分化和死亡等多种途径。一项研究提供了Nox 4是DR期间视网膜中ROS的重要来源的证据，该研究表明Nox 4的耗竭显著降低了糖尿病啮齿动物中的ROS产生、VEGF表达和血管通透性降低。 迄今为止，关于Nox 4在视网膜中的作用的大多数研究利用视网膜或其他器官来源的内皮细胞，其有助于与DR相关的血管变化。直到今天，关于Nox 4在血管系统外的视网膜中的作用和调节存在知识空白，血管系统外的细胞类型特别容易受到代谢变化的影响并有助于DR的早期病理生理变化。我的目标是开发一个完整的图片Nox 4活动在视网膜糖尿病期间通过评估的作用和调节Nox 4作为ROS的主要来源在视网膜神经元，米勒细胞和周细胞在糖尿病条件下培养和两个啮齿动物模型的糖尿病（1型和2型）。我还想评估Nox 4抑制在预防DR中氧化应激诱导的早期神经退行性变化中的基本原理。如果能够实现这样的治疗，则可能在DR发展的最早阶段促进视网膜细胞存活。