Genetic Analysis of Neuronal Hypoxic Stress Resistance
神经元耐缺氧应激的遗传分析
基本信息
- 批准号:9979647
- 负责人:
- 金额:$ 32.55万
- 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 2021-08-14
- 项目状态:已结题
- 来源:
- 关键词:AddressAffinityAnimal ModelAnimalsAnoxiaBehaviorBehavioralBindingBiological ModelsCaenorhabditis elegansCell NucleusCerebral PalsyConsumptionCyclic GMP-Dependent Protein KinasesCysteineDevelopmentDiseaseEndosomesEnvironmentEnzymesEsthesiaEtiologyFoundationsGene ExpressionGenerationsGenesGeneticGenetic ModelsGenetic TranscriptionGlutamate ReceptorGuanylate CyclaseHydroxylationHypoxiaHypoxia Inducible FactorIschemic StrokeLobular NeoplasiaMAP Kinase GeneMalignant NeoplasmsMammalsMeasuresMediatingMediator of activation proteinMitochondriaMolecular ChaperonesMutationMyocardial InfarctionNeuronal HypoxiaNeuronsOrganismOrthologous GeneOxidation-ReductionOxidative StressPathway interactionsPatternPhosphorylationPhysiologyPlayProcollagen-Proline DioxygenaseProlineProteinsProteolysisProteomicsPulmonary HypertensionReceptor InhibitionRecyclingRegulationReproducibilityResistanceRoleScaffolding ProteinSideSpinal cord injuryStressSynapsesSynaptic ReceptorsTestingTissuesTranscriptional RegulationTraumatic Brain InjuryUbiquitinationWorkdeprivationdisorder preventionfactor Agenetic analysishuman diseasehypoxia inducible factor 1in vivointestinal epitheliummutantnovelp38 Mitogen Activated Protein Kinaseparkin gene/proteinphosphoric diester hydrolasereceptor recyclingrecruitresponsesensorstemsynaptic functiontissue cultureubiquitin ligase
项目摘要
PROJECT SUMMARY
Hypoxia (low O2) plays a central role in a diverse array of human diseases. O2 is sensed by the hypoxia
response pathway comprising a prolyl hydroxylase (PHD) enzyme, which uses O2 to hydroxylate specific
prolines on the Hypoxia Inducible Factor α (HIFα). Once hydroxylated, HIFα is ubiquitinated by the Von
Hippel-Lindau (VHL) ubiquitin ligase, resulting in its proteolysis. When hypoxia ensues, PHD enzymes lack the
O2 to hydroxylate HIFα, resulting in HIFα stabilization, entry into the nucleus, and the transcriptional regulation
of multiple target genes. We currently do not know all of the proteins that regulate this pathway, how this
pathway is modulated in different tissue types, or how it uses a single O2 sensor with a low affinity for O2 to
respond to a broad dynamic range of O2 concentration. Because of the essential requirement of pathway
components in early development and viability in mammals, we also know little about how the pathway actually
works in vivo in an intact animal.
To address these questions, 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. C. elegans possess single genes for the PHD (EGL-9), the VHL (VHL-1), and
the HIFα (HIF-1). We recently identified four new regulators/mediators of this pathway. First, the PMK-1
ortholog of p38 MAPK promotes EGL-9 function under normoxia. Second, the EGL-4 ortholog of Protein
Kinase G (PKG) is a substrate of PMK-1 that is required for PMK-1 to regulate EGL-9 activity. Third, the PDR-
1 ortholog of the ubiquitin ligase Parkin inhibits HIF-1 in neurons. Fourth, the CHN-1 ortholog of the ubiquitin
ligase and chaperone CHIP, a factor known to work with Parkin, inhibits HIF-1 in neurons.
We hypothesize that PMK-1 regulates the pathway by activating EGL-4 via phosphorylation. We believe
that they allow for an additional layer of regulation, expanding the dynamic range of O2 sensation and
modulating the timing of the response. We also hypothesize that PDR-1 and CHN-1 form an ubiquitin ligase
pair that regulates HIF-1 independently of (and in different tissues from) regulation by VHL-1, thereby allowing
context-specific and tissue-specific patterns of hypoxia response. Here we will characterize the mechanism by
which CHN-1, PDR-1, EGL-4, and PMK-1 regulate the pathway in vivo. We will measure HIF-1 ubiquitination
and turnover, target gene expression, EGL-9 activity and subcellular localization, hypoxia survival, O2
consumption and ATP generation, oxidative stress, and mitochondrial dynamics in mutants for these factors.
We will directly test whether PDR-1 and CHN-1 regulate the pathway through HIF-1. We will test whether
PMK-1 regulates the pathway by phosphorylating EGL-4. We will use a proteomics approach to identify
downstream substrates of EGL-4 that operate as part of the pathway. At its conclusion, these studies will have
provided the foundation for examining whether the orthologs of these factors conduct similar roles in mammals.
项目总结
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)
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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:
$ 32.55万 - 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:
$ 32.55万 - 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:
$ 32.55万 - 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:
$ 32.55万 - 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:
$ 32.55万 - 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:
$ 32.55万 - 项目类别:
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