Dependence for TEAD transcription factors in intestinal development and polyposis

肠道发育和息肉病中 TEAD 转录因子的依赖性

基本信息

批准号：
10100436
负责人：
Junhao Mao
金额：
$ 39.23万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-17 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10100436
关键词：
Address Biology Chemicals Chromatin Chromatin Remodeling Factor Complex Cysteine Data Dependence Development Differentiation and Growth Digestive System Disorders Down-Regulation Embryo Embryonic Development Endoderm Endothelial Cells Enhancers Epithelial Epithelium Event Family Fibroblasts Functional disorder Future Gastrocoele Gastrointestinal Diseases Gastrointestinal tract structure Genetic Genetic Transcription Grant Growth Homeostasis Human Intestines Lead Link Malignant Neoplasms Mediating Mediator of activation protein Mesenchymal Mesenchyme Mesoderm Modeling Molecular Muscle Development NCOA3 gene Natural regeneration Organ Size Organogenesis Output Pathogenesis Pathway interactions Pattern Physiological Play Proteins Publishing Regulation Reporting Research Personnel Role STK11 gene Signal Transduction Smooth Muscle Smooth Muscle Myocytes Testing Thinness Time Tissues Transcription Factor AP-1 Transcriptional Activation Treatment Efficacy Tube Visceral Work base design fatty acylation gastrointestinal in vivo insight intestinal epithelium intestinal homeostasis mouse genetics mouse model novel novel therapeutic intervention palmitoylation polyposis postnatal progenitor programs recruit self-renewal small molecule inhibitor stem cells tool transcription factor

项目摘要

SUMMARY During vertebrate development, the visceral endoderm recruits adjacent mesoderm to form a primitive gut tube, which later gives rise to the gastrointestinal (GI) tract. Organogenesis and tissue homeostasis within the GI tract require continuous crosstalk between endodermal epithelium and the adjacent mesenchyme. Outstanding studies in the field have elucidated the critical regulatory mechanisms controlling intestinal epithelial self-renewal and regeneration. However, little is known about the biology of GI mesenchyme. During gut development, the visceral mesoderm undertakes remarkable transformation during gut development; it differentiates from a thin layer of progenitor cells into a complex tissue comprised of smooth muscle cells, fibroblasts, and endothelial cells. More importantly, mesenchymal/stromal dysfunction is also closely associated with many digestive diseases and cancers. Thus, understanding the genetic and molecular bases underlying mesenchymal growth and differentiation may lead to future design of novel and effective therapeutic strategies for GI diseases. Our recent work identified a previously unappreciated requirement of Hippo/YAP signaling in GI mesenchyme to coordinate growth and patterning during embryonic development. The TEAD family transcription factors are considered as the major mediator of Hippo/YAP signaling output; however, the physiological roles of TEAD proteins in mammalian development remain poorly characterized. In this application, we will use a combination of rigorous mouse genetics and chemical biology approaches to decipher the roles and underlying mechanism of TEAD regulation in gut development and homeostasis. In Specific Aim 1, we will define the mechanism underlying AP1-YAP/TEAD cooperation in gut mesenchyme. In Specific Aim 2, we will explore the YAP/TAZ- independent TEAD function in gut development. In Specific Aim 3, we will use a chemical biology approach to determine the functional significance of TEAD palmitoylation in hamartomatous polyposis. The successful completion of the proposed studies in this application will provide significant progress towards our understanding of the fundamental mechanisms underlying GI development, homeostasis and pathogenesis.

概括在脊椎动物发育过程中，内脏内胚层募集邻近的中胚层形成原始肠管，随后形成胃肠道。胃肠道内的器官发生和组织稳态需要内胚层上皮和相邻间质之间的连续串扰。杰出的该领域的研究阐明了控制肠上皮自我更新的关键调节机制和再生。然而，人们对胃肠道间充质的生物学知之甚少。在肠道发育过程中，内脏中胚层在肠道发育过程中发生显着的转变；它与薄的不同祖细胞层形成由平滑肌细胞、成纤维细胞和内皮细胞组成的复杂组织细胞。更重要的是，间充质/基质功能障碍也与许多消化系统疾病密切相关。疾病和癌症。因此，了解间充质生长的遗传和分子基础和分化可能会导致未来设计出新颖有效的胃肠道疾病治疗策略。我们的最近的工作发现了胃肠道间充质中 Hippo/YAP 信号传导的一个先前未被认识到的要求协调胚胎发育过程中的生长和模式。 TEAD家族转录因子是被认为是 Hippo/YAP 信号输出的主要中介者；然而，TEAD 的生理作用哺乳动物发育过程中的蛋白质仍然知之甚少。在此应用程序中，我们将使用组合采用严格的小鼠遗传学和化学生物学方法来破译其作用和潜在机制 TEAD 对肠道发育和稳态的调节。在具体目标 1 中，我们将定义机制肠道间质中 AP1-YAP/TEAD 合作的基础。在具体目标 2 中，我们将探讨 YAP/TAZ- 肠道发育中独立的 TEAD 功能。在具体目标 3 中，我们将使用化学生物学方法确定 TEAD 棕榈酰化在错构瘤性息肉病中的功能意义。成功者完成本申请中拟议的研究将为我们的理解带来重大进展胃肠道发育、体内平衡和发病机制的基本机制。