Redox Signaling and Stem Cell Function

氧化还原信号传导和干细胞功能

• 批准号: 8420441
• 负责人: Dirk Bohmann
• 金额: $ 40.23万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 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/8420441
• 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

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精确控制和调整到生物体的要求。潜在的调控机制尚不清楚，但可以在遗传易感的果蝇肠道干细胞（ISCs）中进行研究。两位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著增加ISCs的增殖活性。引人注目的是，ISCs的这种激活需要伴随细胞氧化还原状态的降低。基于氧化还原的干细胞和祖细胞功能调节已经被假设，但这种影响的遗传和机制基础仍然不清楚。这一建议所依据的初步数据表明，Nrf2转录因子在抗氧化和解毒程序中起着关键作用。当应激暴露于ISCs时，Nrf2功能被抑制，允许活性氧（ROS）浓度升高，并促进这些细胞的增殖能力。Nrf2在应激和组织损伤反应中的下调是干细胞独有的，与大多数其他体细胞类型中Nrf2的应激依赖性激活形成鲜明对比。这种独特的Nrf2信号系统仅限于干细胞的发现提出了有趣的问题，并为有针对性地操纵干细胞功能提供了机会。本项目将探讨Nrf2在ISCs中的独特调控和作用。一些实验将探索应激信号如何影响Nrf2调节ISC增殖。单独的实验将验证Nrf2和氧化还原控制是调节干细胞活性的普遍机制的假设，它们不仅需要传递对细胞直接损伤应激的反应，而且还需要介导内分泌分化信号的影响。最后，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，以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为控制干细胞功能和组织稳态的基于氧化还原的机制提供机制理解。目的是测试Nrf2活性决定ISCs减少，无活性状态的模型，在这种状态下，它们免受氧化应激，但不能参与再生过程。应激或有丝分裂信号导致Nrf2功能下调，然后诱导氧化状态，允许再生进行。该模型的验证将证实并从机制上解释长期存在的干细胞和祖细胞调节理论，并可能为操纵干细胞行为提供策略和目标，例如在细胞移植范例或干细胞疾病的治疗中。