Regulation and interplay of Heat Shock Factors in growth-associated proteotoxic stresses
生长相关蛋白毒性应激中热休克因子的调节和相互作用
基本信息
- 批准号:10346843
- 负责人:
- 金额:$ 32.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteArginineBindingBiochemicalBiochemical GeneticsBiological AssayBiological ModelsCancer Cell GrowthCell AdhesionCell ProliferationCell physiologyCellsCellular AssayChromatinComplexDNA BindingDataDevelopmentDiseaseFeedbackFoundationsGene ExpressionGene ProteinsGenesGeneticGenetic ScreeningGenetic TranscriptionGenomicsGlucoseGoalsGrowthHealthHealth PromotionHeat Stress DisordersHeat shock factorHeat shock proteinsHeat-Shock Proteins 70Heat-Shock Proteins 90Heat-Shock ResponseHeat-Shock Transcription Factor 2HumanIn VitroKnowledgeLinkLogicMalignant - descriptorMalignant NeoplasmsMediatingMediator of activation proteinMetabolic stressMetabolismMethodsModelingMolecular ChaperonesMutationMutation AnalysisNerve DegenerationNeurodegenerative DisordersOrganismPhysiologicalPhysiologyProcessProteinsProteomeProteomicsRegulationReperfusion InjuryReporterRoleSeriesSiteSourceStressTechnologyTemperatureTestingTherapeutic InterventionTranscriptional RegulationViral CancerVirus Diseasesbasebiochemical modelbiological adaptation to stresscancer cellcell growthchromatin remodelingcopingdisorder preventionendoplasmic reticulum stressexperimental studygenetic regulatory proteinheat shock transcription factorheat-shock factor 1human diseasein vivonovelparalogous genephysiologic stressorpreventprogramsprotein foldingprotein functionprotein structureproteostasisproteotoxicityrecruitresponsestress resiliencetherapeutic developmenttumortumor microenvironment
项目摘要
Protein homeostasis (proteostasis), or the proper folding and function of the proteome, is vital for cellular and
organismal health. Critical to proteostasis is an evolutionarily ancient cytoprotective mechanism originally
characterized in cells subjected to elevated temperatures. This mechanism, termed the Heat Shock Response
(HSR), is now known to protect against many diverse sources of proteotoxic stress. A hallmark of the HSR is the
profound transcriptional induction of molecular chaperones known as heat shock proteins (HSPs), a process
regulated by the transcription factor Heat Shock Factor 1 (HSF1). Because this rapid and robust transcriptional
induction can be provoked by simply increasing temperature, the HSR has been used as a model system in the
gene expression field for decades. As such, the processes that govern HSF1 activation and transcriptional
regulation upon heat shock have been extensively studied. However, evidence accumulating over the last
decade has revealed a more complicated picture of HSF1 function. We have found that in cancer, HSF1 directly
regulates the transcription of genes involved in cellular processes which extend far beyond protein folding, in a
manner distinct from the classic HSR. This has been mirrored in studies of HSF1 in other physiological contexts,
such as in the tumor microenvironment and in organismal development. The mechanisms which enable HSF1's
regulatory plasticity, and the underlying logic that connects the disparate set of HSF1-regulated genes with
HSF1's role in proteostasis, is not well understood. Here we propose to use cancer as a as a model system to
study the mechanisms that underlie HSF1's non-canonical regulatory roles. Through a series of unbiased proteomic
and genetic screens we identify a factor critical for HSF1 in this distinct physiological context, and a surprising
multifaceted role for a non-canonical HSF1 target gene in feedback regulation of HSF1 and the HSR. To investigate
these mechanisms, we will integrate sophisticated technologies in the field of transcription regulation with
established biochemical, genetic and genomic methods. Our studies will provide the knowledge required for the
development of therapeutic interventions that promote or inhibit specific programs directed by HSF1. Ultimately,
this may enable us to modulate HSF1's non-canonical programs which are implicated in an ever-expanding array
of disease states.
蛋白质稳态,或蛋白质组的适当折叠和功能,对细胞和
身体健康。蛋白质平衡的关键是一种进化上古老的细胞保护机制
以经历高温的细胞为特征的。这种机制被称为热休克反应
(HSR),现在已知可以防止许多不同来源的蛋白毒性应激。高铁的一个标志是
被称为热休克蛋白(HSPs)的分子伴侣的深刻转录诱导是一个过程
受转录因子热休克因子1(HSF1)调控。因为这种快速而强健的转录
感应可以通过简单地提高温度来激发,高铁已经被用作模型系统在
基因表达领域已经有几十年了。因此,管理HSF1激活和转录的过程
对热休克的调节已被广泛研究。然而,在过去的几年里积累的证据
十年揭示了HSF1功能的更复杂的图景。我们已经发现,在癌症中,HSF1直接
调节细胞过程中涉及的基因的转录,这些过程远远超出蛋白质折叠的范围,在
与经典高铁截然不同的方式。这已经反映在对HSF1在其他生理环境中的研究中,
例如在肿瘤微环境和生物体发育中。热休克蛋白1的致病机制:S
调节可塑性,以及将不同的HSF1调节基因集与
HSF1在蛋白调控中的作用,目前还不是很清楚。在这里,我们建议将癌症作为一个模型系统来
研究热休克蛋白1 S非典范调控作用的机制。通过一系列无偏见的蛋白质组学
和基因筛查,我们确定了在这种不同的生理背景下对HSF1至关重要的因素,以及一个令人惊讶的
非规范HSF1靶基因在HSF1和HSR反馈调节中的多方面作用。去调查
这些机制,我们将把转录调控领域的尖端技术与
建立了生化、遗传学和基因组学方法。我们的研究将提供所需的知识
开发治疗干预措施,促进或抑制HSF1指导的特定计划。最终,
这可能使我们能够调制在不断扩展的阵列中牵连的HSF1的S非正则程序
疾病状态。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Marc Mendillo其他文献
Marc Mendillo的其他文献
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{{ truncateString('Marc Mendillo', 18)}}的其他基金
Regulation and interplay of Heat Shock Factors in growth-associated proteotoxic stresses
生长相关蛋白毒性应激中热休克因子的调节和相互作用
- 批准号:
10693802 - 财政年份:2022
- 资助金额:
$ 32.84万 - 项目类别:
Elucidating the stress response regulatory networks that enable malignancy
阐明导致恶性肿瘤的应激反应调节网络
- 批准号:
9222730 - 财政年份:2013
- 资助金额:
$ 32.84万 - 项目类别:
Elucidating the stress response regulatory networks that enable malignancy
阐明导致恶性肿瘤的应激反应调节网络
- 批准号:
8734351 - 财政年份:2013
- 资助金额:
$ 32.84万 - 项目类别:
Elucidating the stress response regulatory networks that enable malignancy
阐明导致恶性肿瘤的应激反应调节网络
- 批准号:
8488142 - 财政年份:2013
- 资助金额:
$ 32.84万 - 项目类别:
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