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

摘要 许多疾病，包括老年痴呆症、心律失常和多发性转移癌， 细胞间钙瞬变（ICT）失调。钙离子（Ca 2+）作为关键的第二信使 参与细胞信号传导和协调器官正常发育。Ca 2+也很重要， 组织中的机械力的转导和用于整合来自可扩散的生物化学物质的多种生物化学信号 称为形态发生素的蛋白质。形态发生素信号和机械力输入都涉及到 发育器官的大小控制和模式。然而，关于这项规定还有很多未知之处， 信息和通信技术在组织生长和再生过程中的作用。例如，一段时间以来， 在脊椎动物的发育过程中，细胞内Ca ~（2+）浓度存在左右不对称性， 控制这种观察到的不对称性的确切机制仍然不清楚。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， 过程中的增长和再生，特别强调了解调控， ICT的功能。我们的实验室处于开发多学科方法的前沿， 组织生长和再生过程中ICT、形态发生素信号和机械力之间的关系。我们有 最近发现的信息通信技术在发展中的果蝇（果蝇）翅盘的前后图案。我们 已经确定了刺猬（Hh）通路的遗传破坏，该通路指导前- 后轴在翅原基，取消了这种观察到的不对称的信息和通信技术。这建立了 在发展背景下形态发生信号和信息和通信技术之间的基本联系。我们目前 重点是弥合描述性观察和系统级定量分析之间的巨大差距， 信通技术。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， 调节果蝇翅盘中的ICT和形态发生活性。 此外，我们正在捕获ICT的动态和多尺度测量，以表征Ca 2+的调制器。 我们还在开发计算模型，以测试形态发生之间的假设串扰。 信号和Ca 2+信号动力学。累积起来，这项研究将导致新的定量成像 将信息和通信技术映射到组织发育和再生中的形态发生模式的方法。一种机械的 对ICT调节和功能的理解将导致对组织如何生长和再生的重要见解。 这种基本的理解也将使我们能够理解和减轻不必要的副作用， 治疗靶向Ca 2+信号传导，并可能揭示加速组织 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.