Nrf2 signaling and oxidative stress in Age-related macular degeneration

年龄相关性黄斑变性中的 Nrf2 信号传导和氧化应激

基本信息

批准号：
8420508
负责人：
James T Handa
金额：
$ 56.47万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8420508
关键词：
Acids Acquired Blindness Address Age related macular degeneration Aging Antioxidants Apoptosis Binding Blindness Chemicals Chronic Complement Activation Cytoprotection Data Deposition Development Disease Disease Progression Early treatment Elderly Enhancers Enzymes Epidemiology Event Functional disorder Fundus Genes Genetic Genetic Transcription Injury Link Macular degeneration Measures Mediating Medicine Mus Nuclear Onset of illness Outcome Oxidants Oxidation-Reduction Oxidative Stress Patients Phase I Clinical Trials Phenotype Prevention Reactive Oxygen Species Regulation Response Elements Retina Risk Factors Role Signal Transduction Smoking Solid Stimulus Structure of retinal pigment epithelium System Testing United States Wild Type Mouse activating transcription factor air filter bZIP Domain biological adaptation to stress cell type cigarette smoke-induced cigarette smoking cigarette smoking complement pathway gain of function inhibitor/antagonist loss of function mouse model nuclear factor-erythroid 2 oxidant stress oxidative damage prevent public health relevance research study response small molecule stressor transcription factor treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the leading cause of acquired blindness in the United States. Patients with early disease suffer from limited and ineffective options for prevention and treatment. To address this shortcoming, this proposal focuses on the mechanisms underlying early disease. Cigarette smoking is the strongest epidemiological link with AMD, yet we do not fully understand its role in the pathophysiology of this disease. Cigarette smoke is a powerful chemical oxidant, and a potent inducer of complement activation. Both of these factors are thought to be important in AMD development. A key early event in AMD is apoptosis of the retinal pigmented epithelium (RPE), in part through inadequately neutralized oxidative stress. Nuclear factor- erythroid 2-related factor 2 (Nrf2), a basic leucine zipper redox-sensitive transcription factor, regulates the inducible expression of antioxidant and cytoprotective genes by binding to the cis-acting enhancer sequence known as the antioxidant response element. Normally, Nrf2 levels are low, but with an oxidative stimulus, nuclear accumulation of Nrf2 increases after it is released from its cytoplasmic inhibitor Keap1, and activates the coordinated transcription of its downstream antioxidant enzymes. Decreased Nrf2 signaling is seen in aging and disease, resulting in an inadequate adaptive stress response. Intriguingly, the decreased Nrf2 activity can be reversed by the synthetic triterpenoid derivatives of oleonolic acid, which represent a promising new class of agents for cytoprotection from oxidative injury. In this proposal, we hypothesize that chronic cigarette smoking induces persistent oxidative stress in the fundus, and that local Nrf2 signaling becomes inadequate with the onset of AMD. Recently, we showed that chronic cigarette smoke induces oxidative and ultrastructural damage, and eventually apoptosis to the RPE of mice. We will exploit this system using genetically modified mice to address our hypothesis with the following aims: 1) To test the hypothesis that Nrf2 signaling protects against cigarette smoke-induced oxidative stress and apoptosis in the fundus. 2) To investigate the hypothesis that regulation by Nrf2 signaling on complement activation determines the damage and apoptosis to the fundus that is induced by cigarette smoke. 3) To determine if a pharmacological activator of Nrf2 protects the fundus from oxidative damage and complement activation.

描述（由申请人提供）：年龄相关性黄斑变性 (AMD) 是美国获得性失明的主要原因。早期疾病患者的预防和治疗选择有限且无效。为了解决这一缺点，该提案重点关注早期疾病的机制。吸烟与 AMD 的流行病学联系最为密切，但我们尚未完全了解其在该疾病病理生理学中的作用。香烟烟雾是一种强大的化学氧化剂，也是补体激活的有效诱导剂。这两个因素都被认为对 AMD 的发展很重要。 AMD 的一个关键早期事件是视网膜色素上皮 (RPE) 的凋亡，部分原因是氧化应激中和不足。核因子-红细胞 2 相关因子 2 (Nrf2) 是一种碱性亮氨酸拉链氧化还原敏感转录因子，通过与称为抗氧化反应元件的顺式作用增强子序列结合来调节抗氧化和细胞保护基因的诱导表达。正常情况下，Nrf2 水平较低，但在氧化刺激下，Nrf2 从细胞质抑制剂 Keap1 中释放后，核内积累增加，并激活其下游抗氧化酶的协调转录。 Nrf2 信号传导减少在衰老和疾病中可见，导致适应性应激反应不足。有趣的是，合成的油酸三萜衍生物可以逆转 Nrf2 活性的降低，油酸油酸是一类有前景的新型细胞保护剂，可防止氧化损伤。在这项提议中，我们假设长期吸烟会引起眼底持续的氧化应激，并且局部 Nrf2 信号传导随着 AMD 的发生而变得不足。最近，我们发现长期吸烟会引起氧化和超微结构损伤，并最终导致小鼠 RPE 凋亡。我们将使用转基因小鼠利用该系统来解决我们的假设，其目的如下：1) 检验 Nrf2 信号传导可防止香烟烟雾诱导的眼底氧化应激和细胞凋亡的假设。 2）研究Nrf2信号对补体激活的调节决定香烟烟雾引起的眼底损伤和细胞凋亡的假设。 3) 确定Nrf2的药理学激活剂是否可以保护眼底免受氧化损伤和补体激活。