Ca2+ Signaling and Stem Cell Dynamics

摘要 体细胞(SCs)通过调节其在体内的增殖活性来确保高周转组织的动态平衡 对各种损伤和应力信号的响应。以确保高效再生，同时还 在再生插曲期间保持SC种群的大小，SC分裂模式可以动态改变 对称保持划分、对称耗尽划分和不对称划分之间的关系。是这样的 动态系统允许组织对变化的环境条件做出快速反应，例如， 根据组织的大小调整干细胞的数量。 允许SC对环境条件做出这种动态反应的调节机制仍然存在 人们对此知之甚少。申请者提出了一个项目，将探索控制肠道干细胞(ISCs)。 果蝇肠道，旨在专门研究不同的ISC分裂模式是如何在 对营养和胁迫信号的反应。根据初步研究，申请者假设振荡 在细胞内的钙离子浓度受胁迫和营养信号的影响，而细胞内的钙离子 浓度作为一种整合信号来激发ISCs对环境变化的动态反应 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。 并将结合实时成像和转录组分析来探索ISC对遗传的反应 和环境扰动。具体地说，这项工作将(I)探索不对称和对称的控制 ISC对营养物质和胁迫的反应，(Ii)测试调节钙离子的信号通路是否- 反应转录因子CRTC整合压力和饮食信号来控制ISC的活动，和(Iii)评估 ISCs是否受CRTC和其他信号反应基因表达的协同调控 转录因子。 果蝇的ISC系统为干细胞的调节和组织的维持提供了丰富的见解 动态平衡。这个系统中的调控过程在进化上是保守的。了解企业的角色 适应性组织生长、内环境平衡再生和上皮应激背景下ISCs中的钙信号 因此，应对措施可能为人类疾病的可能治疗提供重要的新线索，包括 肠癌和炎症性疾病。

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.