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，胃癌导致的死亡人数 全球768,793名患者，使其成为癌症死亡的第四大原因。幽门螺杆菌感染是 胃癌的最大危险因素。幽门螺杆菌引发的炎症导致萎缩性胃炎、痉挛 多肽表达化生(SPEM)、胃肠化生(GIM)和异型增生，一系列 癌前病变与胃癌密切相关。抗生素治疗根除幽门螺杆菌 在降低癌前病变和胃癌发病率方面一直有效。然而，在H. 幽门螺杆菌根除已确立的粘膜上皮化生改变可能无法逆转，并有发生胃病的风险 这类患者的癌症发病率仍然很高。更好地了解导致炎症的机制 由此产生的癌前病变是开发合理有效的治疗方法所必需的。其中一个 幽门螺杆菌刺激炎症信号和癌前病变的机制是通过破坏 胃上皮与周围间充质/间质之间的交通。我们已经确定了一个 胃间充质中PKA活化在建立促炎和癌前状态中的新作用 这与BMP信号的下调有关，BMP信号是已知的胃部关键调节因子 炎症和创业。我们培育并鉴定了一种新的条件突变小鼠Six2Cre/-- PKAcrfl/wt(CA-pKA)模型，其中单等位基因介导的结构性活性pKA(pKAcR)的表达 用SIX2-Cre转基因小鼠在胃间充质内诱导。CA-PKA小鼠发生癌前病变 萎缩性胃炎、SPEM、GIM和异型增生等病变，伴随明显的慢性炎症，因素 与胃癌密切相关这一建议的中心假设是胃中PKA的激活 间充质通过刺激炎症和抑制BMP信号转导而成为胃癌发生的关键驱动因素 将在以下三个目标中进行测试。目标1是确定导致炎症的机制。 CA-PKA小鼠氧合性萎缩。目的2是确定骨形态发生蛋白途径的遗传调控效应 抑制剂gremlin 1(Grem1)对CA-PKA小鼠胃癌前病变严重程度的影响目标3是确定 错误调节的PKA信号在H.Felis诱导的胃病理中的影响。会议的预期结果 拟议中的研究将定义错误调节的PKA信号的分子和功能意义 破坏胃内环境的稳定，并导致病理改变。更好地理解错误调节的PKA信号作为 胃炎和胃癌变的潜在原因可以帮助开发预防和治疗方法 胃癌及其相关病理条件的治疗策略。

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.