Role of Protein Kinase A (PKA)-mediated mesenchymal-epithelial crosstalk in gastric preneoplasia

项目摘要 根据美国临床肿瘤学会的数据，在2020年，胃癌导致 全球有768，793名患者，使其成为癌症死亡的第四大原因。H.幽门螺杆菌感染是 胃癌的最大危险因素。H.幽门启动的炎症导致萎缩性胃炎、痉挛性胃炎、 多肽表达性化生（SPEM）、胃肠化生（GIM）和异型增生，一系列 与胃癌密切相关的癌前病变。H.抗生素治疗幽门螺杆菌 有效降低癌前病变和胃癌的发病率。然而，继H. 幽门螺杆菌根除已经建立的粘膜化生改变可能不会逆转， 这类患者的癌症发病率仍然很高。更好地了解炎症的机制 并且需要由此产生的癌前病变来开发合理和有效的治疗。之一 H.幽门螺杆菌刺激炎症信号和癌前病变是通过破坏 胃上皮和周围间充质/基质之间的沟通。我们已经确定了一 胃间质PKA激活在建立促炎和癌前状态中的新作用 这与BMP信号转导的下调有关，BMP信号转导已知是胃肠道的关键调节因子， 炎症和瘤前病变。我们产生并表征了一种新的条件突变小鼠Six 2Cre +/-- PKAc β Rfl/wt（CA-PKA）模型，其中单个等位基因介导的组成型活性PKA（PKAc β R）的表达 使用Six 2-Cre转基因小鼠在胃间充质中诱导。CA-PKA小鼠发生癌前病变 病变，如萎缩性胃炎，SPEM，GIM和异型增生，沿着明显的慢性炎症，因子 该建议的中心假设是，PKA在胃中的激活与胃癌密切相关。 间充质是通过刺激炎症和抑制BMP信号传导的胃癌发生的关键驱动因素， 将在以下三个目标中进行测试。目的1是确定导致炎症的机制 和CA-PKA小鼠的泌酸性萎缩。目的二是确定BMP通路的基因调控作用 抑制剂gremlin 1（Grem 1）对CA-PKA小鼠胃肿瘤前病变严重程度的影响。目标3：确定 PKA信号的错误调节对H.猫引起的胃病理学预期成果 拟议的研究将确定错误调节PKA信号传导的分子和功能意义， 破坏胃内环境稳定和驱动病理学。更好地理解PKA信号的错误调节， 胃炎症和癌前病变的根本原因可以帮助制定预防和治疗 胃癌和相关病理条件的策略。

Project Summary According to the American Society of Clinical Oncology, in the year 2020, stomach cancer caused death of 768,793 patients worldwide making it the fourth leading cause of cancer deaths. H. pylori infection is the strongest risk factor for gastric cancer. H. pylori-initiated inflammation leads to atrophic gastritis, spasmolytic polypeptide expressing metaplasia (SPEM), gastric intestinal metaplasia (GIM) and dysplasia, a series of preneoplastic lesions strongly associated with gastric cancer. The eradication of H. pylori by antibiotic treatment has been effective in reducing the incidence of preneoplastic lesions and gastric cancer. However, following H. pylori eradication already established mucosal metaplastic changes may not reverse, and the risk of gastric cancer in such patients remains high. A better understanding of the mechanisms contributing to inflammation and the resulting preneoplastic lesions is required to develop rational and effective therapies. One of the mechanisms by which H. pylori stimulates inflammatory signaling and preneoplastic lesions is by disrupting the communication between the gastric epithelium and the surrounding mesenchyme/stroma. We have identified a novel role of PKA activation in the gastric mesenchyme in establishing a proinflammatory and preneoplastic state that is associated with downregulation of BMP signaling which is known to be a key regulator of gastric inflammation and preneoplasia. We generated and characterized a novel conditional mutant mouse Six2Cre+/-- PKAcRfl/wt (CA-PKA) model in which single allele-mediated expression of constitutively active PKA (PKAcR) was induced in the stomach mesenchyme using Six2-Cre transgenic mice. CA-PKA Mice develop preneoplastic lesions such as atrophic gastritis, SPEM, GIM and dysplasia along with marked chronic inflammation, factors strongly associated with gastric cancer The central hypothesis of this proposal is that PKA activation in the gastric mesenchyme is a key driver of gastric carcinogenesis by inciting inflammation and inhibiting BMP signaling that will be tested in the following three aims. Aim 1 is to determine the mechanisms that contribute to inflammation and oxyntic atrophy in CA-PKA mice. Aim 2 is to determine the effects of genetic modulation of BMP pathway inhibitor gremlin 1 (Grem1) on the severity of gastric preneoplastic lesions in CA-PKA mice. Aim 3 is to determine the impact of misregulated PKA signaling on H. felis-induced gastric pathology. Expected outcomes of the proposed research will define the molecular and functional significance of mis-regulated PKA signaling in disrupting gastric homeostasis and driving pathology. A better understanding of misregulated PKA signaling as an underlying cause of gastric inflammation and preneoplasia can help develop preventative and treatment strategies for gastric cancer and associated pathological conditions.