Genetic Analysis of Neuronal Hypoxia Resistance

神经元耐缺氧的遗传分析

基本信息

  • 批准号:
    10835277
  • 负责人:
  • 金额:
    $ 10.44万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-04-15 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Hypoxia (O2 deprivation) plays a central role in diverse human diseases, including ischemic stroke, myocardial infarction, pulmonary hypertension, Cerebral Palsy, COVID-19, and cancer. Metazoans respond to hypoxia by employing the conserved hypoxia response pathway. The pathway senses O2 through a prolyl hydroxylase (PHD) enzyme, which negatively regulates the transcription factor Hypoxia Inducible Factor α (HIFα). When hypoxia ensues, PHD enzymes lack O2 to hydroxylate HIFα, resulting in HIFα stabilization and the transcriptional regulation of multiple target genes that help the organism survive. While the HIFα pathway has been well studied in tissue culture, a full understanding of how it operates in specific tissues (particularly neurons) in vivo to provide tailored responses is needed. This proposal takes advantage of genetics and an intact, isogenic model organism (C. elegans) that can thrive under hypoxia, and whose environment and genetics can be controlled with fidelity and reproducibility. The overall premise of this proposal is that the hypoxia response pathway pathway protects against hypoxic damage by (1) removing mitochondria through mitophagy, which eliminates a source of oxidative stress, and by (2) mobilizing antioxidant metabolism, which detoxifies free radicals during hypoxia and reoxygenation. We hypothesize that HIF-1 promotes this metabolic reprograming by binding an enhancer sequence and activating the expression of the PEP carboxykinase pck-1, a key enzyme for moving metabolites through gluconeogenesis. Aim 1 tests this hypothesis by using CRISPR/Cas9 editing to remove this enhancer, then testing for the effects on HIF-1 binding, pck-1 and global gene expression, metabolism, oxidative stress resistance, neurodegeneration, and hypoxia survival. Preliminary cell biological approaches with a genetically encoded fluorescent reporter for mitophagy suggest that HIF-1 promotes mitophagy. We hypothesize that HIF-1 promotes mitophagy by binding enhancer sequences and activating the expression of the mitophagy receptors fndc-1 and dct-1. Aim 2 tests this hypothesis by using CRISPR/Cas9 editing to remove these enhancers, then testing for the effects on HIF- 1 binding, global gene expression, mitophagy and bulk autophagy, metabolism, oxidative stress resistance, neurodegeneration, and hypoxia survival. Recently, our media sterilizer and automated Petri dish pourer reached the end of its life. This large equipment failure is inhibiting our progress towards both aims, as this fundamental equipment is essential for every experiment we conduct. An administrative supplement is requested to replace this equipment and restore our progress towards understanding how the hypoxia response pathway operates. A better understanding of the pathway will provide therapeutic targets for diseases associated with hypoxia.
项目总结 缺氧(O2剥夺)在包括缺血性中风、心肌梗死在内的多种人类疾病中起着核心作用 脑梗塞、肺动脉高压、脑瘫、新冠肺炎和癌症。后生动物对缺氧的反应是 采用保守的低氧反应途径。该途径通过一种脯氨酸羟基酶来感知O2 (PHD)酶,负调控转录因子缺氧诱导因子α(HIFα)。什么时候 缺氧接踵而至,PHD酶缺乏氧来羟化HIFα,导致HIFα稳定,并 帮助机体存活的多个靶基因的转录调控。而缺氧诱导因子α途径则有 在组织培养方面有很好的研究,对它如何在特定的组织中运作有充分的理解(特别是 在体内)提供量身定制的反应是必要的。这一建议利用了遗传学和 完整的、同基因的模式生物(线虫),能在低氧下茁壮成长,其环境和 遗传学可以通过保真度和重复性来控制。这项提议的总体前提是 低氧反应通路通过(1)通过以下途径去除线粒体来保护低氧损伤 有丝分裂,消除氧化应激的来源,和(2)动员抗氧化剂代谢,这是 在缺氧和复氧过程中对自由基进行解毒。 我们假设HIF-1通过结合增强子序列来促进这种代谢重编程 并激活PEP羧基激酶pck-1的表达,这是一种通过 糖异生作用。AIM 1通过使用CRISPR/Cas9编辑移除该增强子来验证这一假设,然后 检测对HIF-1结合、PCK-1和全球基因表达、代谢、氧化应激的影响 耐药、神经变性和低氧生存。 用基因编码的荧光报告基因检测有丝分裂的初步细胞生物学方法 提示HIF-1促进有丝分裂吞噬。我们假设HIF-1通过结合促进有丝分裂 增强子序列和激活有丝分裂受体fndc-1和dct-1的表达。AIM 2测试 这一假设是通过使用CRISPR/Cas9编辑来移除这些增强子,然后测试对HIF的影响- 1结合,全球基因表达,有丝分裂和大量自噬,代谢,氧化应激抵抗, 神经退行性变,低氧生存。 最近,我们的介质灭菌器和自动培养皿倒酒器即将报废。这么大 设备故障正在阻碍我们朝着这两个目标前进,因为这一基础设备对于 我们进行的每一项实验。需要行政补充以更换该设备,并 恢复我们在了解缺氧反应途径如何运作方面的进展。更好的 对该途径的了解将为与缺氧相关的疾病提供治疗靶点。

项目成果

期刊论文数量(12)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The hypoxia response pathway promotes PEP carboxykinase and gluconeogenesis in C. elegans.
  • DOI:
    10.1038/s41467-022-33849-x
  • 发表时间:
    2022-10-18
  • 期刊:
  • 影响因子:
    16.6
  • 作者:
  • 通讯作者:
Anoxia-reoxygenation regulates mitochondrial dynamics through the hypoxia response pathway, SKN-1/Nrf, and stomatin-like protein STL-1/SLP-2.
  • DOI:
    10.1371/journal.pgen.1004063
  • 发表时间:
    2013
  • 期刊:
  • 影响因子:
    4.5
  • 作者:
    Ghose P;Park EC;Tabakin A;Salazar-Vasquez N;Rongo C
  • 通讯作者:
    Rongo C
Going mobile: AMPA receptors move synapse to synapse in vivo.
  • DOI:
    10.1016/j.neuron.2013.11.031
  • 发表时间:
    2013-12-18
  • 期刊:
  • 影响因子:
    16.2
  • 作者:
    Rongo C
  • 通讯作者:
    Rongo C
RAB-6.1 and RAB-6.2 Promote Retrograde Transport in C. elegans.
RAB-6.1 和 RAB-6.2 促进线虫逆行运输。
  • DOI:
    10.1371/journal.pone.0149314
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Zhang,Donglei;Dubey,Jyoti;Koushika,SandhyaP;Rongo,Christopher
  • 通讯作者:
    Rongo,Christopher
RAB-6.2 and the retromer regulate glutamate receptor recycling through a retrograde pathway.
  • DOI:
    10.1083/jcb.201104141
  • 发表时间:
    2012-01-09
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Zhang D;Isack NR;Glodowski DR;Liu J;Chen CC;Xu XZ;Grant BD;Rongo C
  • 通讯作者:
    Rongo C
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Christopher G Rongo其他文献

Christopher G Rongo的其他文献

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{{ truncateString('Christopher G Rongo', 18)}}的其他基金

Multi-Omic Analysis of BMP-Insulin Signaling Crosstalk in Lipid Metabolism during Aging
衰老过程中脂质代谢中 BMP-胰岛素信号串扰的多组学分析
  • 批准号:
    10351581
  • 财政年份:
    2022
  • 资助金额:
    $ 10.44万
  • 项目类别:
Multi-Omic Analysis of BMP-Insulin Signaling Crosstalk in Lipid Metabolism during Aging
衰老过程中脂质代谢中 BMP-胰岛素信号串扰的多组学分析
  • 批准号:
    10553134
  • 财政年份:
    2022
  • 资助金额:
    $ 10.44万
  • 项目类别:
Genetic Analysis of Neuronal Hypoxia Resistance
神经元耐缺氧的遗传分析
  • 批准号:
    10461150
  • 财政年份:
    2012
  • 资助金额:
    $ 10.44万
  • 项目类别:
Genetic Analysis of Neuronal Hypoxic Stress Resistance
神经元耐缺氧应激的遗传分析
  • 批准号:
    9753252
  • 财政年份:
    2012
  • 资助金额:
    $ 10.44万
  • 项目类别:
Genetics Analysis of Neuronal Hypoxic Stress Resistance
神经元耐缺氧应激的遗传学分析
  • 批准号:
    8650508
  • 财政年份:
    2012
  • 资助金额:
    $ 10.44万
  • 项目类别:
Genetic Analysis of Neuronal Hypoxic Stress Resistance
神经元耐缺氧应激的遗传分析
  • 批准号:
    9979647
  • 财政年份:
    2012
  • 资助金额:
    $ 10.44万
  • 项目类别:
Genetic Analysis of Neuronal Hypoxia Resistance
神经元耐缺氧的遗传分析
  • 批准号:
    10683094
  • 财政年份:
    2012
  • 资助金额:
    $ 10.44万
  • 项目类别:
Genetic Analysis of Neuronal Hypoxia Resistance
神经元耐缺氧的遗传分析
  • 批准号:
    10297456
  • 财政年份:
    2012
  • 资助金额:
    $ 10.44万
  • 项目类别:
Genetics Analysis of Neuronal Hypoxic Stress Resistance
神经元耐缺氧应激的遗传学分析
  • 批准号:
    8457043
  • 财政年份:
    2012
  • 资助金额:
    $ 10.44万
  • 项目类别:
Genetics Analysis of Neuronal Hypoxic Stress Resistance
神经元耐缺氧应激的遗传学分析
  • 批准号:
    8629773
  • 财政年份:
    2012
  • 资助金额:
    $ 10.44万
  • 项目类别:

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