Uncovering non-autonomous mechanisms of control over translational attenuation during heat shock in the metazoan C. elegans
揭示后生动物秀丽隐杆线虫热休克过程中控制平移衰减的非自主机制
基本信息
- 批准号:9167368
- 负责人:
- 金额:$ 18.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-05-15 至 2018-04-30
- 项目状态:已结题
- 来源:
- 关键词:AblationAnimal ModelAttenuatedCaenorhabditis elegansCellsCellular Stress ResponseChaperone GeneControl AnimalCoupledDataDevelopmentDiagnosisEIF-2alphaEndoplasmic ReticulumEnvironmentEukaryotic Initiation FactorsGene ExpressionGenesGenetic TranscriptionHSF1Heat Stress DisordersHeat shock proteinsHeat-Shock ResponseKnowledgeMetabolic DiseasesMolecular ChaperonesNervous system structureNeurodegenerative DisordersNeuronsOrganismPathway interactionsPeptide Initiation FactorsPhasePhosphorylationPhosphotransferasesPolyribosomesProcessProtein BiosynthesisProtein KinaseProteinsRepressionRoleSerotonergic SystemSerotoninSignal PathwaySignal TransductionStressTestingTissuesTranslation InitiationTranslationsUp-RegulationWorkattenuationbiological adaptation to stressbody systemcell typeenvironmental stressorgene inductionintercellular communicationmeetingsneurotransmissionoptogeneticsprogramsreceptorresponse
项目摘要
The initiation of translation is an important point of control in the response of cells to environmental stress.
Stress conditions activate stress-responsive kinases that inhibit translation initiation by phosphorylating
the alpha subunit of the eukaryotic initiation factor 2 (eIF2α) which results in polysome disassembly and
subsequent attenuation of translation. In addition to attenuating translation, stressful environments also
activate the transcription of protective molecular chaperones or heat shock proteins (HSPs). One of the
major recent developments in the understanding of stress responses is the discovery that the
transcriptional expression of chaperones during stress is not triggered autonomously by cells undergoing
macromolecular damage, but is instead cell non-autonomously orchestrated by the nervous system.
However, it is not known whether translational attenuation across the different cells of a metazoan
is also coordinated through similar cell-cell signaling pathways that modulate transcription. In
ongoing studies, we have found that although transcription of chaperones and translational attenuation
occur independent of each other upon heat shock, as with the transcriptional upregulation of chaperone
gene expression, the phosphorylation of eIF2α upon heat stress in C. elegans is dependent on the
serotonergic system. These data suggest that serotonergic control over eIF2α phosphorylation may act
to integrate transcriptional and translational responses to stress across cells of an organism. This is the
hypothesis we aim to test in this proposal. Specifically, we will test (1) how translation attenuation is
coupled to neuronal serotonin release and (2) whether translation attenuation is coordinated with HSP
upregulation through neuronal 5-HT release. We anticipate that these studies will fill a critical gap in
knowledge regarding the coordination of translational upon stress between tissues of a metazoan. These
studies will therefore be important for understanding how stress contributes to the progression of
metabolic and neurodegenerative diseases and allow the development of new strategies for diagnosis
and treatment.
翻译起始是细胞对环境应激反应的重要控制点。
应激条件激活应激应答激酶,其通过磷酸化
真核起始因子2(eIF 2 α)的α亚基,导致多核糖体解体,
随后的平移衰减。除了削弱翻译,紧张的环境也
激活保护性分子伴侣或热休克蛋白(HSP)的转录。之一
最近在理解压力反应方面的一个主要进展是发现,
应激过程中伴侣蛋白的转录表达不是由细胞经历
大分子损伤,而是由神经系统非自主编排的细胞。
然而,目前还不知道在后生动物的不同细胞之间的平移衰减是否
也通过调节转录的类似细胞-细胞信号通路来协调。在
正在进行的研究,我们发现,虽然转录的伴侣和翻译衰减,
在热休克时,它们相互独立地发生,如伴侣蛋白的转录上调
基因表达、eIF 2 α在热胁迫下的磷酸化。elegans依赖于
电子能系统。这些数据表明,对eIF 2 α磷酸化的β-肾上腺素能控制可能起作用,
以整合生物体细胞对应激的转录和翻译反应。这是
假设我们旨在测试这个建议。具体来说,我们将测试(1)平移衰减是如何
与神经元5-羟色胺释放偶联,以及(2)翻译衰减是否与HSP协调
通过神经元5-HT释放上调。我们预计,这些研究将填补一个关键的空白,
关于后生动物的组织之间在应力下的平移协调的知识。这些
因此,研究对于了解压力如何促进疾病的进展非常重要
代谢和神经退行性疾病,并允许开发新的诊断策略
和治疗。
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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Veena Prahlad其他文献
Veena Prahlad的其他文献
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{{ truncateString('Veena Prahlad', 18)}}的其他基金
Investigating how stress induced changes in maternal serotonin affect offspring development and stress resilience
研究压力引起的母亲血清素变化如何影响后代发育和压力恢复能力
- 批准号:
10893245 - 财政年份:2022
- 资助金额:
$ 18.73万 - 项目类别:
Investigating how stress induced changes in maternal serotonin affect offspring development and stress resilience
研究压力引起的母亲血清素变化如何影响后代发育和压力恢复能力
- 批准号:
10602537 - 财政年份:2022
- 资助金额:
$ 18.73万 - 项目类别:
Investigating how stress induced changes in maternal serotonin affect offspring development and stress resilience
研究压力引起的母亲血清素变化如何影响后代发育和压力恢复能力
- 批准号:
10444181 - 财政年份:2022
- 资助金额:
$ 18.73万 - 项目类别:
Metabolism, Aging, Pathogenesis, Stress and Small RNAs Meeting
新陈代谢、衰老、发病机制、压力和小 RNA 会议
- 批准号:
9990946 - 财政年份:2021
- 资助金额:
$ 18.73万 - 项目类别:
Investigating how intestinal innate immunity confers neuroprotection using C. elegans
使用线虫研究肠道先天免疫如何赋予神经保护作用
- 批准号:
9926205 - 财政年份:2018
- 资助金额:
$ 18.73万 - 项目类别:
Investigating how intestinal innate immunity confers neuroprotection using C. elegans
使用线虫研究肠道先天免疫如何赋予神经保护作用
- 批准号:
9764236 - 财政年份:2018
- 资助金额:
$ 18.73万 - 项目类别:
Investigating how intestinal innate immunity confers neuroprotection using C. elegans
使用线虫研究肠道先天免疫如何赋予神经保护作用
- 批准号:
9576370 - 财政年份:2018
- 资助金额:
$ 18.73万 - 项目类别:
Investigating how intestinal innate immunity confers neuroprotection using C. elegans
使用线虫研究肠道先天免疫如何赋予神经保护作用
- 批准号:
10186678 - 财政年份:2018
- 资助金额:
$ 18.73万 - 项目类别:
Investigating how intestinal innate immunity confers neuroprotection using C. elegans
使用线虫研究肠道先天免疫如何赋予神经保护作用
- 批准号:
10425212 - 财政年份:2018
- 资助金额:
$ 18.73万 - 项目类别:
Uncovering how serotonergic signaling non-autonomously regulates protein homeostasis
揭示血清素信号如何非自主调节蛋白质稳态
- 批准号:
9904301 - 财政年份:2016
- 资助金额:
$ 18.73万 - 项目类别:
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