Redox Signaling and Stem Cell Function
氧化还原信号传导和干细胞功能
基本信息
- 批准号:8814244
- 负责人:
- 金额:$ 41.96万
- 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:2012-02-06 至 2016-01-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdultAffectAntioxidantsAreaCell Differentiation processCell ProliferationCell Signaling ProcessCell TransplantationCell divisionCell physiologyCellsCellular StressCharacteristicsCollaborationsCompetenceDataDiseaseDown-RegulationDrosophila genusDrug Metabolic DetoxicationEndocrineEnterocytesEpidermal Growth Factor ReceptorEquilibriumGenesGeneticGoalsGrowth FactorHomeostasisInjuryIntestinesLaboratoriesLifeLigandsMaintenanceMediatingModelingMolecularMuscleN-terminalNatural regenerationOrganismOxidation-ReductionOxidative StressParacrine CommunicationPathway interactionsPhosphotransferasesPlayProcessProductionProliferatingPropertyPublishingReactive Oxygen SpeciesReceptor Protein-Tyrosine KinasesRegulationReportingResearchResearch Project GrantsRoleSignal PathwaySignal TransductionSignaling MoleculeSomatic CellStem cellsStressSystemTestingTissuesValidationVeinsWorkadult stem cellbasebiological adaptation to stresscell behaviorcell injurycell typecytokinedesigninsightinterestoxidative damageparacrineprogramsregenerativeresearch studyresponseself-renewalstemstem cell biologytheoriestranscription factor
项目摘要
DESCRIPTION (provided by applicant): The activity of adult somatic stem cells has to be precisely controlled and adjusted to the organism's requirements. The underlying regulatory mechanisms are not well understood, but can be studied in the genetically tractable Drosophila intestinal stem cells (ISCs). Preliminary data generated in the laboratories of the two applicants have shown that cell stress and tissue damage can significantly increase the proliferative activity of ISCs. Strikingly, this activation of ISCs requires a concomitant decrease in cellular redox state. Redox based regulation of stem and progenitor cell function has been postulated before, but the genetic and mechanistic basis for this effect remains obscure. The preliminary data on which this proposal is based indicate a key role of the Nrf2 transcription factor, which has previously been mostly associated with antioxidant and detoxification programs. Upon stress exposure of ISCs, Nrf2 function is repressed, permitting the concentration of reactive oxygen species (ROS) to rise, and promoting proliferative competence of these cells. The down regulation of Nrf2 in response to stress and tissues injury is unique to stem cells and contrasts sharply with stress dependent activation of Nrf2 described in most other somatic cell types. The discovery of this unique Nrf2 signaling system that is restricted to stem cells raises interesting questions and offers opportunities for the targeted manipulation of stem cell function. This project will explore the distinctive regulation and the effects of Nrf2 in ISCs. Several lines of experimentation will explore how stress signaling affects Nrf2 to regulate ISC proliferation. Separate experiments will test the hypothesis that Nrf2 and redox control are universal mechanisms regulating stem cell activity, which are not only required to convey the response to direct cell damaging stress, but also to mediate the effects of endocrine differentiation signals. Finally, the mechanisms by which redox changes can alter stem cell function in such profound ways will be explored. For this latter aim experiments will be conducted to identify relevant redox sensing signaling molecules that control stem cell activity. The work described in this proposal will provide a mechanistic understanding of the redox-based mechanisms that control stem cell function and consequently tissue homeostasis. The goal is to test the model that Nrf2 activity determines a reduced, inactive state of ISCs, in which they are protected from oxidative stress, but cannot engage in regenerative processes. Down regulation of Nrf2 function by stress or mitogenic signaling then induces an oxidized state that allows regeneration to proceed. Validation of this model will confirm and mechanistically explain long standing theories on stem and progenitor cell regulation and may suggest strategies and targets for the manipulation of stem cell behavior, for example in cell transplantation paradigms or in the treatment of stem cell diseases.
描述(由申请人提供):必须精确控制成年体细胞细胞的活性,并根据生物体的要求进行调整。基本的调节机制尚不清楚,但可以在可遗传的果蝇肠道干细胞(ISC)中进行研究。两名申请人实验室产生的初步数据表明,细胞应激和组织损伤可以显着增加ISC的增殖活性。令人惊讶的是,ISC的激活需要伴随细胞氧化还原状态的降低。以前已经假定了基于氧化还原的茎和祖细胞功能的调节,但是这种效果的遗传和机械基础仍然晦涩难懂。该建议基于的初步数据表明NRF2转录因子的关键作用,该因子以前主要与抗氧化剂和排毒程序有关。 ISC的压力暴露后,NRF2功能被抑制,允许活性氧(ROS)的浓度升高,并促进这些细胞的增殖能力。响应压力和组织损伤的NRF2的下调调节是干细胞独有的,并且与大多数其他体细胞类型中描述的NRF2的依赖性依赖性激活形成鲜明对比。这种独特的NRF2信号系统的发现限于干细胞,这引发了有趣的问题,并为有针对性的干细胞功能提供了机会。该项目将探讨NRF2在ISC中的独特调节和影响。几条实验将探讨应力信号如何影响NRF2调节ISC增殖。单独的实验将检验以下假设:NRF2和氧化还原控制是调节干细胞活性的通用机制,不仅需要传达对直接细胞损害应激的反应,而且还需要介导内分泌分化信号的影响。最后,将探索氧化还原变化可以以如此深刻的方式改变干细胞功能的机制。对于后一种目标实验,将进行确定控制干细胞活性的相关氧化还原传感信号分子。本提案中描述的工作将提供对控制干细胞功能并因此具有组织稳态的基于氧化还原的机制的机械理解。目的是测试NRF2活性确定ISC的降低,无活性状态的模型,其中它们受到保护免受氧化应激的影响,但不能参与再生过程。通过应力或有丝分裂信号传导调节NRF2功能,然后诱导允许再生进行氧化状态。该模型的验证将确认并从机械上解释有关茎和祖细胞调节的长期存在理论,并可能提出操纵干细胞行为的策略和目标,例如在细胞移植范式中或处理干细胞疾病的治疗。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
You Are What You Eat: Linking High-Fat Diet to Stem Cell Dysfunction and Tumorigenesis.
人如其食:高脂肪饮食与干细胞功能障碍和肿瘤发生有关。
- DOI:10.1016/j.stem.2016.04.010
- 发表时间:2016
- 期刊:
- 影响因子:23.9
- 作者:Haller,Samantha;Jasper,Heinrich
- 通讯作者:Jasper,Heinrich
Slit/Robo signaling regulates cell fate decisions in the intestinal stem cell lineage of Drosophila.
- DOI:10.1016/j.celrep.2014.05.024
- 发表时间:2014-06-26
- 期刊:
- 影响因子:8.8
- 作者:Biteau B;Jasper H
- 通讯作者:Jasper H
Dpp signaling determines regional stem cell identity in the regenerating adult Drosophila gastrointestinal tract.
- DOI:10.1016/j.celrep.2013.05.040
- 发表时间:2013-07-11
- 期刊:
- 影响因子:8.8
- 作者:Li H;Qi Y;Jasper H
- 通讯作者:Jasper H
Cross talk between the nuclease and helicase activities of Dna2: role of an essential iron-sulfur cluster domain.
- DOI:10.1093/nar/gks534
- 发表时间:2012-09
- 期刊:
- 影响因子:14.9
- 作者:Pokharel S;Campbell JL
- 通讯作者:Campbell JL
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Dirk Bohmann其他文献
Dirk Bohmann的其他文献
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{{ truncateString('Dirk Bohmann', 18)}}的其他基金
Nrf2 as a regulator of health span and aging
Nrf2 作为健康跨度和衰老的调节因子
- 批准号:
8519191 - 财政年份:2011
- 资助金额:
$ 41.96万 - 项目类别:
Nrf2 as a regulator of health span and aging
Nrf2 作为健康跨度和衰老的调节因子
- 批准号:
8309129 - 财政年份:2011
- 资助金额:
$ 41.96万 - 项目类别:
Nrf2 as a regulator of health span and aging
Nrf2 作为健康跨度和衰老的调节因子
- 批准号:
8707921 - 财政年份:2011
- 资助金额:
$ 41.96万 - 项目类别:
Nrf2 as a regulator of health span and aging
Nrf2 作为健康跨度和衰老的调节因子
- 批准号:
8087651 - 财政年份:2011
- 资助金额:
$ 41.96万 - 项目类别:
Regulation of Cell-Cell Interactions by Matrix Metalloproteases
基质金属蛋白酶对细胞间相互作用的调节
- 批准号:
8033391 - 财政年份:2010
- 资助金额:
$ 41.96万 - 项目类别:
Regulation of Cell-Cell Interactions by Matrix Metalloproteases
基质金属蛋白酶对细胞间相互作用的调节
- 批准号:
8392264 - 财政年份:2010
- 资助金额:
$ 41.96万 - 项目类别:
Regulation of Cell-Cell Interactions by Matrix Metalloproteases
基质金属蛋白酶对细胞间相互作用的调节
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8587490 - 财政年份:2010
- 资助金额:
$ 41.96万 - 项目类别:
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