Induction and Evolution of Metaplasia in the Stomach

描述（由申请人提供）：人胃腺癌是在幽门螺杆菌诱导的泌酸萎缩和慢性粘液细胞化生的背景下演变而来的。我们最近的谱系图谱研究表明，小鼠胃底的化生并非由位于腺体上颈部区域的专业祖细胞产生，而是由成熟主细胞转分化为表达解痉多肽的化生（SPEM）。这些研究导致胃肿瘤起源概念发生重大范式转变，表明肿瘤前谱系并非源自专业驻留粘膜祖细胞群，而是由成熟酶原细胞谱系的转分化发展而来。此外，多项研究现在表明，在炎症的影响下，SPEM 可以增加增殖和增加肠化基因表达水平，并在人类中引起杯状细胞肠化生。我们最近的研究表明，巨噬细胞负责促进增殖性 SPEM 进展，但负责 SPEM 向肠化和不典型增生进展的精确介质仍然未知。因此，我们假设离散的内在粘膜和巨噬细胞衍生因子不仅调节进化，而且调节 SPEM 向更具增殖性的肿瘤前化生的进展。为了解决这个假设，我们将追求两个具体目标：首先，我们将研究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 进化中的作用，以及在由主细胞中激活的 K-Ras 诱导表达驱动的新型化生模型中 SPEM 谱系的进一步肠化。虽然我们之前的研究重点是通过主细胞转分化建立化生生成的新途径，但目前的研究重点是 可能驱动化生为癌前病变的机制。

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.