Regulation of Growth and Morphogenesis

项目摘要 我们研究的目标是定义机械力通过的分子机制 细胞感知，以确定生化和生物力学信号是如何整合的，并定义如何 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。 我们的研究包括对形成发育器官的细胞间信号通路的研究，以 定义它们的调控，它们的作用机制，以及它们的转录和形态发生输出。我们 关注Dachsous-Fat、Hippo和Notch信号通路，这些信号通路在 动物王国，在大多数器官的发育过程中扮演着多重必要的角色，一直以来都被认为是先天的 综合症在失活时和调控失调时可能与癌症有关。 我们目前研究的一个主要焦点是调查这些通路和细胞机械之间的联系 环境。我们研究机械环境如何通过对细胞骨架张力的影响来调节 信号通路，我们建议的研究的一部分将建立在我们对分子机制的发现上 通过在粘连连接处经历的张力影响河马信号和器官生长。这 机制是由细胞骨架张力依赖的Ajuba家族LIM蛋白(Jub In)的招募触发的 果蝇)与α-连环蛋白发生粘连反应。然后，JUB招募并抑制关键的河马途径激酶， 这导致河马途径的转录因子约克的活性增加。这条路是 在哺乳动物细胞中保守，我们未来的实验将扩大对它是如何调控的理解， 以及它在果蝇和哺乳动物模型中对生长和形态发生的贡献。我们 研究河马信号的其他方面，包括对LATS和下游的调节 抄写。我们还将研究细胞骨架张力和Notch信号之间的一种新的联系 我们最近发现。 我们还研究了信号通路如何调节机械环境来影响 形态发生。我们计划的研究将使用果蝇的翅膀作为器官形状控制的模型，以及 研究细胞骨架张力和ds-Fat信号通路是如何控制机翼形状的。这些研究将 使用体外器官培养和图像分析来表征有助于 形态发生。我们还将研究调节粘连连接处张力的反馈机制 以及通过对Ajuba家族蛋白及其伴侣的张力依赖调节细胞行为。 我们的研究与了解正常发育、生理和疾病状态有关。 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 这对于理解干细胞如何用于修复或替换受损器官很重要，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.