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

• 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
• 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

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.

总结 在脊椎动物的发育过程中，内脏内胚层吸收邻近的中胚层形成原肠管， 其随后产生胃肠道（GI）。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充质之间的连续串扰。优秀 该领域的研究已经阐明了控制肠上皮自我更新的关键调节机制 和再生。然而，对GI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了显著的变化;它与薄的 细胞分化为由平滑肌细胞、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新的和有效的治疗策略的胃肠道疾病。我们 最近的工作确定了胃肠道间充质中Hippo/雅普信号传导的一个以前未被认识到的要求， 在胚胎发育期间协调生长和图案化。TEAD家族转录因子是 被认为是Hippo/雅普信号输出的主要介质;然而，TEAD的生理作用 哺乳动物发育中的蛋白质仍然缺乏表征。在这个应用程序中，我们将使用一个组合 严格的小鼠遗传学和化学生物学方法来破译角色和潜在机制 在肠道发育和体内平衡中的作用。在具体目标1中，我们将定义机制 潜在的AP 1-雅普/TEAD在肠间充质中的合作。在具体目标2中，我们将探讨雅普/TAZ- 在肠道发育中独立的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 完成本申请中的拟议研究将为我们了解 胃肠道发育、体内平衡和发病机制的基本机制。