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：
Dirk Bohmann
金额：
$ 41.96万
依托单位：
UNIVERSITY OF ROCHESTER
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：
https://reporter.nih.gov/project-details/8814244
关键词：
Acute Adult Affect Antioxidants Area Cell Differentiation process Cell Proliferation Cell Signaling Process Cell Transplantation Cell division Cell physiology Cells Cellular Stress Characteristics Collaborations Competence Data Disease Down-Regulation Drosophila genus Drug Metabolic Detoxication Endocrine Enterocytes Epidermal Growth Factor Receptor Equilibrium Genes Genetic Goals Growth Factor Homeostasis Injury Intestines Laboratories Life Ligands Maintenance Mediating Modeling Molecular Muscle N-terminal Natural regeneration Organism Oxidation-Reduction Oxidative Stress Paracrine Communication Pathway interactions Phosphotransferases Play Process Production Proliferating Property Publishing Reactive Oxygen Species Receptor Protein-Tyrosine Kinases Regulation Reporting Research Research Project Grants Role Signal Pathway Signal Transduction Signaling Molecule Somatic Cell Stem cells Stress System Testing Tissues Validation Veins Work adult stem cell base biological adaptation to stress cell behavior cell injury cell type cytokine design insight interest oxidative damage paracrine programs regenerative research study response self-renewal stem stem cell biology theories transcription 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）：成体干细胞的活性必须根据生物体的要求进行精确控制和调整。潜在的调节机制尚不清楚，但可以在遗传易处理的果蝇肠干细胞（ISC）中进行研究。两位申请人的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。引人注目的是，ISC 的这种激活需要细胞氧化还原状态的同时减少。之前已经假设了基于氧化还原的干细胞和祖细胞功能调节，但这种效应的遗传和机制基础仍然不清楚。该提案所依据的初步数据表明 Nrf2 转录因子的关键作用，此前该因子主要与抗氧化和解毒程序相关。当 ISC 受到应激时，Nrf2 功能受到抑制，导致活性氧 (ROS) 浓度升高，并促进这些细胞的增殖能力。 Nrf2 响应压力和组织损伤而下调是干细胞所特有的，与大多数其他体细胞类型中描述的压力依赖性 Nrf2 激活形成鲜明对比。这种仅限于干细胞的独特 Nrf2 信号系统的发现提出了有趣的问题，并为干细胞功能的靶向操纵提供了机会。该项目将探讨 Nrf2 在 ISC 中的独特调控和影响。几项实验将探索压力信号如何影响 Nrf2 来调节 ISC 增殖。单独的实验将检验 Nrf2 和氧化还原控制是调节干细胞活性的通用机制的假设，它们不仅需要传达对直接细胞损伤应激的反应，而且还需要介导内分泌分化信号的影响。最后，我们将探讨氧化还原变化以如此深刻的方式改变干细胞功能的机制。对于后一个目标，将进行实验来识别控制干细胞活性的相关氧化还原传感信号分子。该提案中描述的工作将为控制干细胞功能并从而控制组织稳态的基于氧化还原的机制提供机械理解。目标是测试 Nrf2 活性决定 ISC 减少、非活性状态的模型，在这种状态下，ISC 可以免受氧化应激，但不能参与再生过程。通过应激或有丝分裂信号传导下调 Nrf2 功能，然后诱导氧化状态，使再生得以进行。该模型的验证将证实并从机制上解释关于干细胞和祖细胞调节的长期理论，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或干细胞疾病的治疗中。