Regulation and function of multicellular calcium signaling in epithelial growth and regeneration

摘要 许多疾病，包括阿尔茨海默氏症、心律失常和多发性转移性癌症都表现出 失调的细胞间钙瞬变(ICT)。钙离子(钙离子)是关键的第二信使 参与细胞信号传递和协调适当的器官发育。Ca~(2+)在植物体内也具有重要作用 组织中机械力的传递和用于整合来自扩散的多个生化信号 称为形态原素的蛋白质。形态信号和机械力输入都涉及到 发育中器官的大小控制和图案形成。然而，关于这项规定和 信息和通信技术在组织生长和再生中的作用。例如，人们已经知道一段时间了 在脊椎动物的发育过程中，细胞内钙离子浓度存在左右不对称；然而， 这种观察到的不对称性的确切机制尚不清楚。这项研究的总体目标 计划是确定管理细胞协调的基本原则和机制 生长和再生过程中的过程，特别强调了解调节和 信息和通信技术的功能。我们的实验室处于开发多学科方法来定义相互作用的前沿 在组织生长和再生过程中，ICTs、形态发生信号和机械力之间的关系。我们有 最近在发育中的果蝇(果蝇)翼盘中发现了ICT的前后图案。我们 已经发现Hedgehog(HH)通路的遗传破坏，它指导着前部- 位于翼原基的后轴，消除了这种观察到的ICT的不对称性。这建立了一个 在发育背景下，形态因子信号与信息和通信技术之间的基本联系。我们现在正在 侧重于弥合描述性观察和系统级定量分析之间的巨大差距 信息和通信技术。我们正在研究信息通信技术对形态发生信号、器官发育和再生的影响 从遗传学和药理学的角度调节果蝇翼盘中的ICT和形态生成活性。 此外，我们正在捕捉信息和通信技术的动态和多尺度测量，以表征钙离子的调节器。 我们还在开发计算模型来测试形态发生之间的假设串扰 信号和钙离子信号动力学。累积起来，这项研究将产生新的定量成像 将信通技术映射到发育和再生组织中的形态发生模式的方法。机械师 对ICT调控和功能的理解将导致对组织如何生长和再生的关键洞察。 这一根本性的理解还将使我们能够理解和减轻 以钙离子信号为靶点进行治疗，并可能揭示加速组织的创新策略 再生。

ABSTRACT Many diseases including Alzheimer's, cardiac arrhythmias, and multiple metastatic cancers exhibit dysregulated intercellular Ca2+ transients (ICTs). Calcium ions (Ca2+) serve as critical second messengers involved in cell signaling and in coordinating proper organ development. Ca2+ is also important in the transduction of mechanical forces in tissues and for integrating multiple biochemical signals from diffusible proteins termed morphogens. Both morphogen signaling and mechanical force inputs have been implicated in the size control and patterning of developing organs. However, much is still unknown about the regulation and functions of ICTs during tissue growth and regeneration. For example, it has been known for some time that a left-right asymmetry in intracellular Ca2+ concentrations exists during vertebrate development; however, the exact mechanism governing this observed asymmetry remains unclear. The overall goal of the research program is to identify the underlying principles and mechanisms that govern the coordination of cellular processes during growth and regeneration with a particular emphasis on understanding the regulation and functions of ICTs. Our lab is at the forefront of developing multi-disciplinary approaches to define the interplay between ICTs, morphogen signaling, and mechanical forces during tissue growth and regeneration. We have recently discovered anterior-posterior patterning of ICTs in developing Drosophila (fruit fly) wing discs. We have identified that genetic disruption of the Hedgehog (Hh) pathway, which directs patterning of the anterior- posterior axis in the wing primordium, abolishes this observed asymmetry of ICTs. This establishes a fundamental link between morphogen signaling and ICTs in a developmental context. We are now currently focused on bridging the large gap between descriptive observations and systems-level quantitative analysis of ICTs. We are studying the impact of ICTs on morphogen signaling, organ development, and regeneration by modulating ICTs and morphogen activity both genetically and pharmacologically in Drosophila wing discs. Further, we are capturing dynamic and multi-scale measurements of ICTs to characterize modulators of Ca2+. We are also developing computational models to test hypothesized cross-talk between morphogenetic signaling and Ca2+ signaling dynamics. Cumulatively, this research will result in novel quantitative imaging approaches to map ICTs to morphogenetic patterning in developing and regenerating tissues. A mechanistic understanding of ICT regulation and function will lead to critical insights into how tissues grow and regenerate. This fundamental understanding also will allow us to understand and mitigate unwanted side effects of targeting Ca2+ signaling therapeutically and will potentially reveal innovative strategies for accelerating tissue regeneration.