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; 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）：低氧细胞损伤和轴突变性是美国发病率和死亡率最大的两个原因。尽管长期以来长期以来的科学努力，但尚未证明没有治疗可以有效缓解人类的低氧损伤或轴突变性。 NAD生物合成酶烟酰胺单核苷酸腺苷转移酶1（NMNAT1）已显示可阻断小鼠的轴突变性和低氧损伤。尽管具有严重的医学相关表型，但NMNAT1保护免受低氧损伤或轴突变性的机制却晦涩难懂。该应用建议利用强大的遗传模型生物C.秀丽隐杆线虫开发一种新模型来研究NMNAT1的细胞保护机制。我实验室的初步实验表明，小鼠NMNAT1突变形式的秀丽隐杆线虫中的表达可保护线虫免受低氧损伤。此外，我们发现NMNAT1在秀丽隐杆线虫中的寿命多于双倍的寿命，表明NMNAT1对衰老具有强大的细胞保护功能。该项目将在秀丽隐杆线虫中开发其他工具，以研究小鼠NMNAT1的功能，并回答有关NMNAT1防御性损伤和衰老的保护机制的基本问题。 AIM 1的完成将确定哪种细胞类型NMNAT1表达可以保护避免缺氧细胞损伤和有机体衰老。此外，我们将确定是否仅保护NMNAT1仅保护其表达的细胞（细胞自主活动），或者NMNAT1是否作用于保护其未表达的细胞（细胞非自主功能）。 AIM 1还将定义NMNAT1何时在缺氧损伤之前或之后及时延长寿命，并延长寿命，并分别在缺氧损伤之前或之后延长寿命。 AIM 2将使用产生的转基因菌株来测试我们的初步结果提出的特定NMNAT1机械假设。我们将询问线粒体展开的蛋白质反应是否需要NMNAT1的保护作用，以及NMNAT1是否调节线粒体展开的蛋白质反应的活性。这些目标的完成将开发出一种强大的新模型来研究这种重要的酶，并可能定义了一种机制，NMNAT1可以保护缺氧并延长寿命。