Hippo通路调控胃解痉多肽表达型化生及恶性转化的功能机制

胃上皮组织由多种类型细胞构成且更新速度极快，其稳态异常可导致胃癌等疾病。胃癌是我国高发的恶性肿瘤，其病理机制尚未阐明，缺乏有效治疗药物。解痉多肽表达型化生（SPEM）是胃组织损伤修复的重要病理生理过程，该过程中主细胞去分化重编程失败或者干性调控异常将导致肠化生及胃癌。Hippo是调控器官大小与肿瘤发生的关键信号通路。申请人前期发现了Hippo通路的调控新机制及其在胃癌进展中的功能作用，并发展了靶向抑制剂（Cancer Cell；Nat Commun；J Exp Med）；近期发现Hippo通路关键组分YAP调控胃稳态，影响SPEM及相关胃癌发生发展（未发表数据）。在此基础上，本项目将重点探究SPEM及其向胃癌转化过程中Hippo通路调控主细胞去分化重编程及储备干细胞激活的功能作用与分子机制，揭示其异常调控及病理作用，创新发展胃组织损伤修复与胃癌早期发生相关理论，提出胃癌靶向诊疗策略。

The constantly renewing gastric epithelium is composed of many gastric unit formed by multiple types of cells including pit cell, parietal cell, chief cell and stem cells. Cooperation among these cells is essential for the maintenance of gastric tissue homeostasis. Disruption of such homeostasis may cause diseases including cancer. Gastric cancer ranks the second among the top five cancers in China. Due to its extremely heterogeneous nature, the pathology of gastric cancer is yet to be clarified, leaving us limited therapies against the disease. Spasmolytic polypeptide-expressing metaplasia (SPEM) is an important pathophysiological process induced by damage and/or inflammation with substantial loss of parietal cells. SPEM is metaplastic mucous cell lineage with phenotypic characteristics of deep antral gland cells including strong expression of trefoil factor 2 (TFF2). During gastric tissue repair and reestablishment of tissue homeostasis, SPEM is thought to mediate the palingenesis of gastric epithelium; whereas atrophy of the corpus and body of the stomach is always associated with SPEM. Actually, dysregulation of SPEM can lead to diseases including gastric cancer. The Hippo signaling pathway plays a key role in organ size control, tissue development and tumorigenesis. Previously, the applicant has a systematic study of the nuclear regulation of the Hippo signaling, which led to the discovery of VGLL4 as a natural antagonist of YAP and IRF3 as an activator of YAP, as well as the development of peptide and compound inhibitors targeting YAP activity (Cancer Cell; Nat Commun; J Exp Med). Recently, the applicant found the Hippo pathway, especially YAP, is involved in the regulation of gastric tissue homeostasis and SPEM, possibly in a cell type-specific manner. Based on these work, this project hypothesizes that the Hippo pathway may utilize tissue-specific factors to regulate the cellular network of SPEM (most likely parietal cell and stem cell). Therefore, this project aims to elucidate the cell type-specific function and mechanism of the Hippo signaling in SPEM and SPEM-related gastric cancer, hoping to develop innovative theory of gastric tissue repair and early gastric tumorigenesis, as well as new targeted therapy.