Regulation of Growth and Morphogenesis

生长和形态发生的调节

• 批准号: 10606496
• 负责人: KENNETH D IRVINE
• 金额: $ 62.38万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10606496
• 关键词: Adherens Junction; Animals; Biochemical; Biomechanics; Cells; Congenital Abnormality; Cytoskeleton; Development; Developmental Process; Disease; Drosophila genus; Environment; Family; Fatty acid glycerol esters; Feedback; Future; Genetic Transcription; Goals; Growth; Image Analysis; Investigation; Link; Malignant Neoplasms; Mammalian Cell; Mechanics; Modeling; Molecular; Morphogenesis; Notch Signaling Pathway; Organ; Organ Culture Techniques; Organ Model; Organism; Output; Pathway interactions; Pattern; Phosphotransferases; Physiology; Play; Protein Family; Proteins; Regenerative Medicine; Regulation; Research; Role; Shapes; Signal Pathway; Signal Transduction; Syndrome; Wing; alpha catenin; cell behavior; experience; experimental study; mechanical force; notch protein; novel; organ growth; recruit; repaired; stem cells; transcription factor

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.

项目摘要 我们研究的目标是确定分子机制，通过该机制，机械力被 细胞感知，以确定生物化学和生物力学信号是如何整合的，并定义如何 生物化学和生物力学信号网络指导适当大小和形状的器官的形成。 我们的研究包括对发育器官的细胞间信号通路的研究， 定义它们的调节，它们的作用机制，以及它们的转录和形态发生输出。我们 专注于Dachsous-Fat，Hippo和Notch信号通路，这些通路在整个过程中高度保守。 动物界，在大多数器官的发育中起着多种重要作用， 当失活时和当失调时的综合征可能与癌症相关。 我们研究的一个主要重点是研究这些途径与细胞机械 环境我们研究如何机械环境，通过对细胞骨架张力的影响， 信号通路，我们提出的研究的一部分将建立在我们发现的分子机制， 通过其在粘附连接处经历的张力影响Hippo信号传导和器官生长。这 这种机制是由筋骨草家族LIM蛋白的细胞骨架张力依赖性募集触发的（Jub in 果蝇）与α-连环蛋白的粘附连接。然后Jub招募并抑制关键的Hippo通路激酶， 疣，这会导致Yorkie（Hippo途径的转录因子）的活性增加。该途径 在哺乳动物细胞中是保守的，我们未来的实验将扩大对它是如何调节的理解， 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Hippo信号传导的其他方面，包括LATS和下游信号传导的调节。 转录。我们还将研究细胞骨架张力和Notch信号之间的新联系， 我们最近发现的。 我们还研究了信号通路如何调节机械环境， 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， 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 和细胞行为通过张力依赖性调节的筋骨草家族蛋白质和他们的合作伙伴。 我们的研究与了解正常发育和生理以及疾病状态有关 与生长不足或过度或异常器官形状有关。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非常重要， 关于再生医学