Induction and Evolution of Metaplasia in the Stomach

描述(申请人提供)：人类胃腺癌发生在幽门螺杆菌引起的氧化萎缩和慢性粘液细胞化生的背景下。我们最近的谱系图谱研究表明，小鼠胃底的化生不是由位于腺体上颈区的专业祖细胞产生的，而是由成熟的主细胞转分化为表达化生的痉挛多肽而发展起来的。这些研究导致了胃肿瘤起源概念的显著范式转变，表明肿瘤前谱系不是来自专业的常驻粘膜祖细胞群体，而是来自成熟的产酶细胞谱系的转分化。此外，现在的多项研究表明，在炎症的影响下，SPEM可以促进增殖和增加肠化基因的表达，在人类中会引起杯状细胞肠化生。我们最近的研究表明，巨噬细胞促进了SPEM的增殖性进展，但导致SPEM向肠化和异型增生发展的确切介质尚不清楚。因此，我们假设离散的粘膜和巨噬细胞衍生的内在因子不仅调节SPEM的进化，而且还调节SPEM向更多的增殖性、癌前化生的进展。为了解决这一假设，我们将追求两个特定的目标：第一，我们将检查巨噬细胞在化生的进化和进展中的作用。其次，我们将评估RAS激活在主细胞转分化的SPEM演变中的作用，以及在由主细胞中激活的K-RAS的诱导表达驱动的新的化生模型中SPEM谱系的进一步肠化。我们以前的研究集中在通过主细胞的转分化建立一种新的化生途径，而现在的研究集中在 可能推动再生障碍物转化为创业型的机制。

DESCRIPTION (provided by applicant): Adenocarcinoma in the human stomach evolves in the setting of Helicobacter pylori- induced oxyntic atrophy and chronic mucous cell metaplasia. Our recent lineage mapping studies have demonstrated that metaplasia in the gastric fundus in mice does not arise from the professional progenitor cells located in the upper neck region of the glands, but rather develops from transdifferentiation of mature chief cells into Spasmolytic Polypeptide Expressing Metaplasia, or SPEM. These studies have led to a significant paradigm shift in the concepts for the origin of gastric neoplasia, suggesting that pre-neoplastic lineages do not arise from professional resident mucosal progenitor cell populations, but rather develop from transdifferentiation of mature zymogenic cell lineages. Furthermore, multiple studies now indicate that SPEM, under the influence of inflammation, can develop both increased proliferation and increasing levels of intestinalizing gene expression, and in humans gives rise to goblet cell intestinal metaplasia. Our recent investigations have demonstrated that macrophages are responsible for the promotion of proliferative SPEM progression, but the precise mediators that are responsible for the progression of SPEM towards intestinalization and dysplasia remain unknown. We therefore hypothesize that discrete intrinsic mucosal and macrophage-derived factors regulate not only the evolution, but also the progression of SPEM to more proliferative, preneoplastic metaplasia. To address this hypothesis, we will pursue two specific aims: First, we will examine the role of macrophages in the evolution and progression of metaplasia. Second, we will evaluate the role of Ras activation in evolution of SPEM from transdifferentiating chief cells and the further intestinalization of SPEM lineages in a novel model of metaplasia driven by inducible expression of activated K-Ras in chief cells. While our previous investigations have focused on the establishment of a novel pathway for generation of metaplasia through transdifferentiation of chief cells, the present investigations now focus on the mechanisms that might drive metaplasias to preneoplasia.