A C. ELEGANS MODEL FOR NMNAT1-MEDIATED HYPOXIC PROTECTION AND LIFESPAN EXTENSION

NMNAT1 介导的缺氧保护和寿命延长的线虫模型

• 批准号: 8837115
• 负责人: C. Michael Crowder
• 金额: $ 8.89万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8837115
• 关键词: C.; ELEGANS; MODEL; NMNAT1; MEDIATED

DESCRIPTION (provided by applicant): Hypoxic cellular injury and axonal degeneration are two of the most devastating causes of morbidity and mortality in the US. Despite a tremendous longstanding scientific effort, no treatment has proven to be effective at ameliorating either hypoxic injury or axonal degeneration in humans. The NAD biosynthetic enzyme nicotinamide mononucleotide adenylyl transferase 1 (Nmnat1) has been shown to block both axonal degeneration and hypoxic injury in mouse. Despite the profound medically relevant phenotype, the mechanism whereby Nmnat1 protects from either hypoxic injury or axonal degeneration is obscure. This application proposes to utilize the powerful genetic model organism C. elegans to develop a new model to study the cytoprotective mechanisms of Nmnat1. Preliminary experiments from my lab have shown that expression in C. elegans of a mutant form of mouse Nmnat1 protects the nematode from hypoxic injury. In addition, we have discovered that Nmnat1 more than doubles lifespan in C. elegans, demonstrating a strong cytoprotective function of Nmnat1 against aging. This project will develop additional tools in C. elegans to study the function of mouse Nmnat1 and answer fundamental questions about the protective mechanisms of Nmnat1 against hypoxic injury and aging. Completion of aim 1 will determine in what cell types Nmnat1 expression provides protection from hypoxic cellular injury and organismal aging. Additionally, we will determine whether Nmnat1 acts to protect only the cells in which it is expressed (cell autonomous activity) or whether Nmnat1 acts to protect cells in which it is not expressed (cell non-autonomous function). Aim 1 will also define when Nmnat1 functions to protect from hypoxia and extend lifespan, in particular, before or after the hypoxic insult and early or late in life, respectively. Aim 2 will use transgenic strains generated in aim to test a specific Nmnat1 mechanistic hypothesis suggested by our preliminary results. We will ask if the mitochondrial unfolded protein response is required for the protective action of Nmnat1 and whether Nmnat1 regulates the activity of the mitochondrial unfolded protein response. Completion of these aims will develop a powerful new model to study this important enzyme and may define a mechanism whereby Nmnat1 protects from hypoxia and lengthens lifespan.

描述（由申请人提供）：在美国，低分化细胞损伤和轴突变性是发病率和死亡率的两个最具破坏性的原因。尽管科学界长期以来做出了巨大的努力，但没有任何治疗方法被证明能有效改善人类的缺氧损伤或轴突变性。NAD生物合成酶烟酰胺单核苷酸腺苷酰转移酶1（Nmnat 1）已被证明可以阻断小鼠的轴突变性和缺氧损伤。尽管有深刻的医学相关的表型，Nmnat 1保护缺氧损伤或轴突变性的机制是模糊的。本申请提出利用强大的遗传模式生物C。elegans建立一个新的模型来研究Nmnat1的细胞保护机制。我实验室的初步实验表明，在C。小鼠Nmnat 1突变形式的线虫保护线虫免受缺氧损伤。此外，我们还发现Nmnat 1使C的寿命增加了一倍多。elegans，证明了Nmnat 1对衰老的强细胞保护功能。本项目将开发C语言的其他工具。elegans研究小鼠Nmnat 1的功能，并回答有关Nmnat 1对缺氧损伤和衰老的保护机制的基本问题。目标1的完成将确定Nmnat 1表达在哪些细胞类型中提供对缺氧细胞损伤和生物体衰老的保护。此外，我们将确定Nmnat 1是否仅用于保护表达它的细胞（细胞自主活动）或Nmnat 1是否用于保护不表达它的细胞（细胞非自主功能）。目标1还将定义Nmnat 1何时起作用以保护免受缺氧并延长寿命，特别是分别在缺氧损伤之前或之后以及生命早期或晚期。目的2将使用目的中产生的转基因菌株来测试我们的初步结果所提出的特定Nmnat 1机制假设。我们将询问Nmnat 1的保护作用是否需要线粒体未折叠蛋白反应，以及Nmnat 1是否调节线粒体未折叠蛋白反应的活性。这些目标的完成将开发一个强大的新模型来研究这种重要的酶，并可能定义一种机制，使Nmnat 1免受缺氧和延长寿命。