Hippo信号通路调控胃粘膜损伤修复的细胞与分子机制

胃部疾病发病率高达80%，长期困扰全世界，而我国更是胃病大国，每年发病数以亿计。物理、化学、生物等因素均可诱导胃粘膜乃至粘膜下层组织损伤，导致胃炎、胃溃疡、甚至胃癌等疾病。申请人长期探究胃肠道组织损伤修复等生理病理过程，揭示了Hippo信号通路调控胃肠稳态的功能机制（Cancer Cell；Nat Immunol；Nat Commun）；近期研究发现簇细胞中Hippo信号可响应胃粘膜损伤刺激而动态变化，特异性敲除该通路组分YAP/TAZ则显著抑制胃粘膜修复（未发表）。由此推断：Hippo通路感知损伤信号，诱导活化簇细胞等关键亚群，通过细胞间互作，调控干细胞重编程，介导胃粘膜损伤修复；该过程失调可导致炎癌等疾病发生。在此基础上，本项目将深入探究胃粘膜损伤修复过程中的信号感知调控，细胞互作模式和谱系重编程，阐明其分子细胞信号机制，推动我国在该领域达到世界领先，为相关胃病诊疗提供理论基础和策略。

The gastric mucosa is composed of many types of cells that are renewed quickly and constantly. Physical, chemical, biological, and even psychological factors can induce tissue injury of the gastric tissue, destroying the integrity of the gastric mucosa and even the submucosa, causing gastritis, gastric ulcers and even gastric cancer. Hippo pathway is a key signaling pathway that regulates organ size and tissue homeostasis; and YAP/TAZ as transcription coactivators, are essential components of this pathway. The applicant has been focusing on the physiological and pathological regulation of the gastrointestinal tissue injury, repair and homeostasis. Previously, the applicant has revealed the function and mechanism for the Hippo signaling pathway in the regulation of gastrointestinal homeostasis, and developed targeted inhibitors for the treatment of gastric cancer (Cancer Cell; Nat Immunol; Nat Commun). Recently, the applicant found that the Hippo signaling can respond to gastric tissue injury in tuft cells, and she further prepared conditional knockout/knock-in mice of key components of the Hippo pathway and observed specific knockout of YAP/TAZ in tuft cells apparently impaired tissue repair of the gastric mucosa, results indicating an essential role for the Hippo signaling pathway in tuft cell-mediated gastric tissue repair. Based on these unpublished findings, the applicant hypothesizes that the Hippo signaling pathway in tuft cells may sense the signals of gastric tissue injury and thus undergoes dynamic regulation to further influence the interactions of tuft cells with other types of cells including stem cells, which eventually orchestrates the reprograming of stem cells and other cell lineages to meet the needs for repairing the gastric mucosa; dysregulation of this process would cause various diseases including gastritis, gastric ulcers and even gastric cancer. In this project, the applicant will take advantage of her expertise in the Hippo signaling and gastrointestinal research, but focus on 1) the sensing mechanism of gastric tissue injury signal, 2) the tuft cell- and stem cell-centered cell-cell interaction network and communication mode, 3) the way through which cell lineage is reprogrammed during the process of gastric mucosal injury & repair, aiming to clarify the inside molecular and cellular mechanisms. By carrying out this project, we hope to push forward the Chinese study in this field to take a leading position, providing theoretical advances for the diagnosis and treatment of gastric-related diseases.