Regulation of Growth and Morphogenesis

项目概要 我们研究的目标是定义机械力作用的分子机制 被细胞感知，确定生化和生物力学信号如何整合，并定义如何整合 生化和生物力学信号网络直接形成适当大小和形状的器官。 我们的研究包括对发育器官模式的细胞间信号传导途径的研究，以 定义它们的调节、作用机制以及它们的转录和形态发生输出。我们 重点关注 Dachsous-Fat、Hippo 和 Notch 信号通路，这些通路通过 动物界，在大多数器官的发育中发挥多种重要作用，被先天性地喜爱 失活和失调时的综合征可能与癌症有关。 我们当前研究的一个主要重点是调查这些途径与细胞机械性能之间的联系 环境。我们研究机械环境如何通过影响细胞骨架张力来调节 信号通路，我们拟议的研究的一部分将建立在我们对分子机制的发现之上 通过这种方式，粘附连接处经历的张力会影响 Hippo 信号传导和器官生长。这个 该机制是由 Ajuba 家族 LIM 蛋白（Jub in 果蝇）在粘附连接处转变为α-连环蛋白。然后 Jub 招募并抑制关键的 Hippo 通路激酶， 疣，导致约克（Hippo 途径的转录因子）活性增加。这条途径是 在哺乳动物细胞中保守，我们未来的实验将扩大对其调控方式的理解， 以及它对果蝇和哺乳动物模型的生长和形态发生的贡献。我们 还研究 Hippo 信号传导的其他方面，包括 LATS 和下游的调节 转录。我们还将研究细胞骨架张力和 Notch 信号传导之间的新联系 我们最近发现了。 我们还研究信号通路如何调节机械环境以影响 形态发生。我们计划的研究将采用果蝇翅膀作为器官形状控制的模型，并且 研究细胞骨架张力和 Ds-Fat 信号通路如何控制翅膀形状。这些研究将 采用离体器官培养和图像分析来表征细胞动力学，从而有助于 形态发生。我们还将研究调节粘附连接处张力的反馈机制 通过对 Ajuba 家族蛋白及其伴侣的张力依赖性调节来调节细胞行为。 我们的研究与理解正常发育和生理学以及疾病状态相关 与生长不足或过度，或器官形状异常有关。控制器官生长也是 对于理解如何使用干细胞修复或替换受损器官非常重要，这是一个目标 再生医学。

Project Summary The goals of our research are to define molecular mechanisms through which mechanical forces are perceived by cells, to determine how biochemical and biomechanical signals are integrated, and to define how biochemical and biomechanical signaling networks direct formation of organs of appropriate size and shape. Our studies include investigations of intercellular signaling pathways that pattern developing organs, to define their regulation, their mechanism of action, and their transcriptional and morphogenetic outputs. We focus on the Dachsous-Fat, Hippo, and Notch signaling pathways, which are highly conserved through the animal kingdom, play multiple essential roles in the development of most organs, have been liked to congenital syndromes when inactivated, and when dysregulated can be associated with cancer. A major current focus of our research investigates links between these pathways and cells' mechanical environment. We study how the mechanical environment, through influences on cytoskeletal tension, regulates signaling pathways, and part of our proposed research will build upon our discovery of a molecular mechanism through which tension experienced at adherens junctions influences Hippo signaling and organ growth. This mechanism is triggered by cytoskeletal tension-dependent recruitment of an Ajuba family LIM protein (Jub in Drosophila) to α-catenin at adherens junctions. Jub then recruits and inhibits the key Hippo pathway kinase, Warts, which leads to increased activity of Yorkie, a transcription factor of the Hippo pathway. This pathway is conserved in mammalian cells, and our future experiments will expand understanding of how it is regulated, and what it contributes to growth and morphogenesis in both Drosophila and mammalian models. We investigate other aspects of Hippo signaling as well, including regulation of LATS and of downstream transcription. We will also investigate a novel connection between cytoskeletal tension and Notch signaling that we have recently identified. We also investigate how signaling pathways modulate the mechanical environment to influence morphogenesis. Our planned studies will employ the Drosophila wing as a model for organ shape control, and investigate how cytoskeletal tension and the Ds-Fat signaling pathway control wing shape. These studies will employ ex vivo organ culture and image analysis to characterize cell dynamics that contribute to morphogenesis. We will also investigate feedback mechanisms that modulate tension at adherens junctions and cell behaviors through tension-dependent regulation of Ajuba family proteins and their partners. Our studies are relevant to understanding both normal development and physiology, and disease states associated with either insufficient or excess growth, or abnormal organ shape. Controlling organ growth is also important for understanding how stem cells can be used to repair or replace damaged organs, which is a goal of regenerative medicine.