Growth and patterning in the gut mesenchyme

描述(申请人提供)：胃肠道(GI)内的器官发生和组织动态平衡需要内胚层上皮和相邻间充质之间的持续串扰。有关GI发育的许多知识都是从对内胚层及其衍生物的研究中学到的；然而，对控制肠道间充质发育的遗传和细胞机制知之甚少。这项赠款申请旨在揭示这一重要但鲜为人知的发展系统背后的机制。拟议的研究集中在描述肠道间充质生长和模式的分子基础上。我们将使用小鼠遗传学和细胞方法的组合来解决三个主要问题。首先，我们将定义一个SOX依赖的分子开关，负责协调早期原始祖细胞的扩张和随后的间充质分化。在拨款的第二部分，我们将确定共同作用于控制平滑肌肉生长和肠道器官大小的信号通路。在赠款的第三部分，我们将探索一种新的间质机制，它涉及到抑制肠道息肉病。我们相信，拟议研究的完成将大大加深我们对控制肠道发育和动态平衡的基本机制的理解。从我们的研究中获得的这些知识最终将有助于开发治疗胃肠道相关疾病和癌症的新疗法。

DESCRIPTION (provided by applicant): Organogenesis and tissue homeostasis within the gastrointestinal (GI) tract require continuous crosstalk between the endodermal epithelium and adjacent mesenchyme. Much of what is known about GI development has been learned from studies of the endoderm and its derivatives; however, little is known about the genetic and cellular mechanisms governing gut mesenchymal development. This grant application is designed to uncover the mechanisms that underlie this important, yet poorly understood developmental system. The proposed studies are centered on charactering on the molecular basis of growth and patterning in the gut mesenchyme. We will use a combination of mouse genetics and cellular approaches to address three principle questions. First, we will define a Sox-dependent molecular switch that is responsible for coordinating early primitive progenitor expansion and subsequent mesenchymal differentiation. In the second part of the grant, we will identify the signaling pathways that act in concert to control smooth muscle growth and intestinal organ size. In the third part of the grant, we will explore a novel mesenchymal mechanism that is involved in suppression of intestinal polyposis. We believe that completion of the proposed studies will significantly further our understanding of the fundamental mechanisms controlling gut development and homeostasis. This knowledge gained from our studies will ultimately contribute to the development of new therapies for treating GI-related diseases and cancers.