Ca2+ Signaling and Stem Cell Dynamics

Ca2 信号传导和干细胞动力学

• 批准号: 9185208
• 负责人: Heinrich Jasper
• 金额: $ 37.83万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9185208
• 关键词: Address; Calcineurin; Cell Lineage; Cell Proliferation; Code; Coupled; Data; Diet; Disease; Drosophila genus; Ensure; Enterocytes; Epithelial; Experimental Models; Frequencies; Gene Expression Regulation; Genes; Genetic; Glutamates; Growth; Homeostasis; Human; Image; Infection; Inflammatory; Intestinal Cancer; Intestines; Life; Link; Maintenance; Mediator of activation protein; Metabotropic Glutamate Receptors; Mitotic; Modeling; Natural regeneration; Nutrient; Pathway interactions; Process; Protocols documentation; Receptor Signaling; Regulation; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Stem cells; Stimulus; Stress; Surveys; System; Testing; Tissues; Transcription Coactivator; Vertebrates; Work; base; biological adaptation to stress; design; dynamic system; environmental change; genetic analysis; human disease; imaging system; insight; insulin signaling; intestinal epithelium; programs; regenerative; response; second messenger; stem cell division; stem cell population; transcription factor; transcriptome

Summary Somatic stem cells (SCs) ensure homeostasis of high-turnover tissues by adjusting their proliferative activity in response to a wide range of damage and stress signals. To guarantee efficient regeneration while also preserving the size of the SC population during regenerative episodes, SC division modes can dynamically shift between symmetrically preserving divisions, symmetrically depleting divisions, and asymmetric divisions. Such a dynamic system allows rapid responses of the tissue to changing environmental conditions, by, for example, scaling the number of SCs according to the size of the tissue. The regulatory mechanisms that allow such dynamic responses of SCs to environmental conditions remain poorly understood. The applicant proposes a project that will explore the control of intestinal stem cells (ISCs) of the Drosophila gut, and is designed to specifically address how different ISC division modes are regulated in response to nutrient and stress signals. Based on preliminary studies, the applicant hypothesizes that oscillations in the intracellular concentration of Ca2+ are influenced by stress and nutrient signals and that the cytosolic Ca2+ concentration serves as an integrating signal to elicit dynamic responses of ISCs to changing environmental conditions. To test this hypothesis, the applicant proposes studies that take advantage of the genetic accessibility of Drosophila ISCs and will combine live imaging and transcriptome analysis to probe ISC responses to genetic and environmental perturbations. Specifically, the work will (i) explore the control of asymmetric and symmetric ISC divisions in response to nutrients and stress, (ii) test whether a signaling pathway regulating the Ca2+- responsive transcription factor CRTC integrates stress and dietary signals to control ISC activity, and (iii) assess whether ISCs are regulated by cooperative regulation of gene expression by CRTC and other signal-responsive transcription factors. The Drosophila ISC system has provided rich insight into stem cell regulation and the maintenance of tissue homeostasis. The regulatory processes in this system are evolutionarily conserved. Understanding the role of Ca2+ signaling in ISCs in the context of adaptive tissue growth, homeostatic regeneration, and epithelial stress responses is thus likely to provide significant new leads for possible therapies of human diseases, including intestinal cancers and inflammatory diseases.

总结 体细胞干细胞（SC）通过调节其增殖活性来确保高周转组织的稳态， 对各种损伤和应力信号的响应。为了保证高效再生，同时 在再生阶段，保留SC群体的大小，SC分割模式可以动态地改变 在对称保留划分、对称消耗划分和不对称划分之间。等 动态系统允许组织对变化的环境条件快速响应，例如， 根据组织的大小缩放SC的数量。 允许SC对环境条件的这种动态反应的调节机制仍然存在 不太了解。申请人提出了一个项目，该项目将探索控制肠道干细胞（ISCs）， 果蝇肠道，并旨在专门解决如何不同的ISC分裂模式进行调节， 对营养和压力信号的反应。基于初步研究，申请人假设振荡 细胞内Ca ~（2+）浓度受胁迫和营养信号的影响， 浓度作为整合信号，引起ISCs对变化的环境的动态响应 条件 为了验证这一假设，申请人提出了利用基因可及性的研究， 果蝇ISCs，并将联合收割机结合实时成像和转录组分析，以探测ISC对遗传 和环境扰动。具体而言，这项工作将（i）探索控制不对称和对称 ISC分裂响应营养和压力，（ii）测试是否调节Ca 2 +- 响应性转录因子CRTC整合应激和饮食信号以控制ISC活性，和（iii）评估 ISCs是否受CRTC和其他信号应答基因表达的协同调节的调节， 转录因子 果蝇ISC系统为干细胞调控和组织维持提供了丰富的见解 体内平衡该系统中的调节过程在进化上是保守的。理解的作用 在适应性组织生长、稳态再生和上皮应激的背景下，ISCs中的Ca 2+信号传导 因此，这些反应可能为人类疾病的可能疗法提供重要的新线索，包括 肠癌和炎性疾病。