GENETIC ANALYSIS OF HYPOXIC CELL DEATH IN C. ELEGANS

线虫缺氧细胞死亡的遗传分析

基本信息

  • 批准号:
    8387604
  • 负责人:
  • 金额:
    $ 42.14万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2003
  • 资助国家:
    美国
  • 起止时间:
    2003-12-01 至 2017-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Hypoxic cell death kills more people in the USA than any other cause; stroke is the leading cause of disability. However, no therapy has shown benefit against hypoxic cell death. A variety of forward genetic screens in C. elegans have implicated protein homeostasis as critical to survival after hypoxia. Using complementary approaches in C. elegans and mouse hippocampal neurons, we propose to define proteostasis mechanisms that can protect neurons from hypoxic cellular injury. Our specific aims are: 1) Determine the role of protein homeostasis in cell autonomous and non-autonomous, early and delayed, neuronal cell death. Utilizing a mutant where all cells are protected from hypoxic injury, we will selectively express a wild type copy of this gene in neurons and myocytes. We will utilize these unique transgenic strains and others that we will generate along with cell-specific RNAi to examine the role of protein homeostasis in cell autonomous, non-autonomous, early, and delayed, neuronal death. 2) Define the mechanisms whereby translation factor knockdown increase survival from hypoxic injury. Translational suppression has been associated with hypoxia resistance in a variety of experimental paradigms. The mechanism whereby translational suppression protects from hypoxic injury has been nearly universally attributed to a decrease in oxygen consumption. We have performed a survey of the effect of knockdown of various translation factors on C. elegans organismal survival after hypoxia and correlated the level of hypoxia resistances with oxygen consumption, resistance to perturbation of protein homeostasis, and other traits. The correlation of hypoxia resistance with oxygen consumption was weak and correlated strongly only with resistance to perturbations in protein homeostasis. This argues that translational suppression protects from hypoxic injury by improving protein homeostasis. Focusing on established proteostasis pathways, we propose to utilize a variety of C. elegans genetic reagents to define the mechanisms whereby translational suppression protects from hypoxia. 3) Examine the ability of protein homeostasis compounds to protect from immediate and delayed hypoxic injury of mouse hippocampal and C. elegans neurons. We have strong evidence from RNAi knockdown experiments that modulation of proteostasis before oxygen/glucose deprivation is an important determinant of survival of mouse hippocampal neurons. We now propose to determine whether and, if so, when proteostasis compounds are neuroprotective. We will test various categories of chemical proteostasis regulators. We will add the drugs before or after hypoxia and measure if and when these compounds can provide neuroprotection in primary mouse hippocampal neuronal cultures and in our C. elegans neuronal cell death models generated in specific aim 1. PUBLIC HEALTH RELEVANCE: Hypoxic cell death in the form of stroke and myocardial infarction is the number one cause of mortality in the US. Through the research aims proposed here, new genes and pathways that control survival of cells after hypoxic injury may be delineated. These discoveries could lead to the development of therapies for this devastating group of diseases.
描述(由申请人提供):低氧细胞死亡杀死了美国的人数比任何其他原因都多;中风是残疾的主要原因。但是,尚无治疗对低氧细胞死亡的益处。秀丽隐杆线虫中的各种正向遗传筛选都暗示蛋白质稳态对于缺氧后的生存至关重要。使用秀丽隐杆线虫和小鼠海马神经元中的互补方法,我们建议定义可以保护神经元免受低氧细胞损伤的蛋白质量机制。我们的具体目的是:1)确定蛋白质稳态在细胞自主和非自主,早期和延迟的神经元细胞死亡中的作用。利用一个突变体,其中所有细胞都受到保护免于低氧损伤的影响 我们将在神经元和肌细胞中有选择地表达该基因的野生型副本。我们将利用这些独特的转基因菌株以及将与细胞特异性RNAi一起产生的其他转基因菌株来检查蛋白质稳态在细胞自主,非自主,早期和延迟神经元死亡中的作用。 2)定义了转化因子敲低增加缺氧损伤的生存的机制。翻译抑制与多种实验范式中的低氧性抗性有关。转化抑制免受低氧损伤的机制几乎普遍归因于氧气消耗的减少。我们已经对缺氧后各种翻译因子对秀丽隐杆线虫生存的敲低影响进行了调查,并将缺氧耐药性水平与氧气消耗相关,对蛋白质稳态的扰动和其他性状的耐药性。缺氧与氧气消耗的相关性较弱,并且仅与对蛋白质稳态扰动的耐药性相关。这认为翻译抑制可以通过改善蛋白质稳态来保护低氧损伤。我们专注于已建立的蛋白质途径,我们建议利用各种秀丽隐杆线虫遗传试剂来定义转化抑制免受缺氧的机制。 3)检查蛋白质稳态化合物免受小鼠海马和秀丽隐杆线虫神经元的直接和延迟缺氧损伤的能力。我们从RNAi敲低实验中有强有力的证据表明,在氧/葡萄糖剥夺之前的蛋白质量调节是小鼠海马神经元存活的重要决定因素。现在,我们建议确定当蛋白抑制性化合物是神经保护作用时是否和如果是这样。我们将测试各种化学蛋白抑制剂的各种类别。我们将在缺氧之前或之后添加药物,并测量这些化合物是否以及何时可以在原发性小鼠海马神经元培养物以及我们的特定目标中产生的秀丽隐杆线虫神经元细胞死亡模型中提供神经保护作用。 公共卫生相关性:以中风和心肌梗塞形式的低氧细胞死亡是美国死亡率的第一大原因。通过此处提出的研究目的,可以划定控制缺氧损伤后细胞存活的新基因和途径。这些发现可能导致这种毁灭性疾病的疗法发展。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

暂无数据

数据更新时间:2024-06-01

C. Michael Crowde...的其他基金

DEFINING RAPTOR-MEDIATED MECHANISMS OF HYPOXIC INJURY
定义猛禽介导的缺氧损伤机制
  • 批准号:
    10732078
    10732078
  • 财政年份:
    2023
  • 资助金额:
    $ 42.14万
    $ 42.14万
  • 项目类别:
Defining the Translational Machinery Controlling Hypoxic Sensitivity
定义控制缺氧敏感性的转化机制
  • 批准号:
    10246395
    10246395
  • 财政年份:
    2018
  • 资助金额:
    $ 42.14万
    $ 42.14万
  • 项目类别:
Defining the Translational Machinery Controlling Hypoxic Sensitivity
定义控制缺氧敏感性的转化机制
  • 批准号:
    10002322
    10002322
  • 财政年份:
    2018
  • 资助金额:
    $ 42.14万
    $ 42.14万
  • 项目类别:
Defining the Translational Machinery Controlling Hypoxic Sensitivity
定义控制缺氧敏感性的转化机制
  • 批准号:
    10471344
    10471344
  • 财政年份:
    2018
  • 资助金额:
    $ 42.14万
    $ 42.14万
  • 项目类别:
Mitochondrial Protein Misfolding and Aggregation after Hypoxia: Mechanisms and Mitigation
缺氧后线粒体蛋白错误折叠和聚集:机制和缓解
  • 批准号:
    10218275
    10218275
  • 财政年份:
    2017
  • 资助金额:
    $ 42.14万
    $ 42.14万
  • 项目类别:
Mitochondrial Protein Misfolding and Aggregation after Hypoxia: Mechanisms and Mitigation
缺氧后线粒体蛋白错误折叠和聚集:机制和缓解
  • 批准号:
    9401407
    9401407
  • 财政年份:
    2017
  • 资助金额:
    $ 42.14万
    $ 42.14万
  • 项目类别:
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:
    8573890
    8573890
  • 财政年份:
    2013
  • 资助金额:
    $ 42.14万
    $ 42.14万
  • 项目类别:
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
    8837115
  • 财政年份:
    2013
  • 资助金额:
    $ 42.14万
    $ 42.14万
  • 项目类别:
GENETIC ANALYSIS OF HYPOXIC DEATH IN C ELEGANS
线虫缺氧死亡的遗传分析
  • 批准号:
    7928071
    7928071
  • 财政年份:
    2009
  • 资助金额:
    $ 42.14万
    $ 42.14万
  • 项目类别:
GENETIC ANALYSIS OF HYPOXIC CELL DEATH IN C. ELEGANS
线虫缺氧细胞死亡的遗传分析
  • 批准号:
    8906950
    8906950
  • 财政年份:
    2003
  • 资助金额:
    $ 42.14万
    $ 42.14万
  • 项目类别:

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