Oxyntic Atrophy and Novel Gastric Lineages

胃腺癌仍然是全球第三大癌症相关死亡原因。绝 大多数胃癌在慢性萎缩性胃炎的背景下在胃中发展， 与幽门螺杆菌感染有关。而H.幽门螺杆菌作为胃溃疡的近因 癌发生是公认的，谱系变化的细胞基础，导致发展 癌前化生和进展为癌症仍不清楚。慢性损伤与H.幽门 感染导致胃上皮细胞组成的显著变化，伴随壁细胞的丧失 （泌酸性萎缩）、表面细胞扩张（小凹增生）和粘液细胞化生。两 化生谱系现在被认为是人类胃泌酸萎缩的背景：肠化生 （特征为胃粘膜中存在肠杯状细胞）和痉挛多肽 表达性化生（SPEM）;特征为在胃体中存在窦型粘液细胞。 胃）。然而，小鼠的螺杆菌感染仅导致SPEM。在过去的20年里，我们 研究了在胃泌酸性萎缩的情况下导致SPEM发展的因素。利用血统- 在小鼠的定位研究中，我们已经证明了SPEM不是来自专业祖细胞， 从表达Mist 1的成熟主细胞转分化为粘液细胞化生。所有这些结果 支持胃底粘膜壁细胞的缺失诱导胃粘膜上皮细胞的发展这一概念。 来自Chief细胞转分化的SPEM。由于SPEM似乎是最初的癌前化生， 对于胃泌酸萎缩的反应，理解Chief细胞的转分化如何导致胃泌酸萎缩是至关重要的。 SPEM的出现是发育异常和瘤形成所需的中心初始事件， 胃在过去的资助期间，我们已经确定，Chief细胞转分化为 SPEM需要一系列有序的细胞事件，这些事件通过以下途径介导酶原颗粒的缩小： 自噬和粘液颗粒产生的放大以实现粘液化生。我们已经确定 可以通过抑制xCT胱氨酸来阻止转分化过程的离散干预 转运蛋白或抑制自噬。我们假设由14-3-3介导的离散事件 蛋白分层或miR-148 a的改变是启动Chief转分化的关键早期触发因素。 严重胃损伤后的细胞。因此，我们将继续我们的研究化生的起源，通过 起诉有两个具体目的：！！首先，我们将研究Stratifin在启动细胞重编程中的作用。 主细胞转分化为化生。我们将寻求评估分层蛋白的丢失是否会改变 转分化过程。此外，我们还将鉴定Chief细胞中的细胞内磷蛋白， 都是分层行动的目标第二，我们将确定miR-148 a如何调节启动， 转分化的进展。我们已经确定miR-148 a是Chief细胞中表达的主要miRNA。 并确定其表达在转分化起始时快速下调。我们将 研究miR-148 a缺失对转录物和蛋白表达的影响， 转分化对假定的调节因子的验证研究将把这些介质置于 完成转分化所需的离散步骤。! 所有这些研究将有助于确定参与Chief细胞转分化的基本机制， 可能导致如何预防或逆转肿瘤前化生谱系变化的见解。 !

Gastric adenocarcinoma remains the third most common cause of cancer-related death worldwide. The vast majority of gastric cancer evolves in the stomach in the setting of chronic atrophic gastritis usually in association with Helicobacter pylori infection. While the role of H. pylori as the proximate cause of gastric carcinogenesis is well established, the cellular basis of lineage changes that lead to development of preneoplastic metaplasia and progression to cancer remain unclear. Chronic injury associated with H. pylori infection leads to prominent changes in the composition of the gastric epithelia, with loss of parietal cells (oxyntic atrophy), expansion of surface cells (foveolar hyperplasia) and mucous cell metaplasia. Two metaplastic lineages are now acknowledged in the setting of oxyntic atrophy in humans: intestinal metaplasia (characterized by the presence of intestinal goblet cells in the gastric mucosa) and Spasmolytic Polypeptide Expressing Metaplasia (SPEM; characterized by presence of antral type mucous cells in the body of the stomach). However, Helicobacter infection in mice leads only to SPEM. Over the past 20 years, we have investigated the factors that lead to the development of SPEM in the face of oxyntic atrophy. Using lineage- mapping studies in mice, we have demonstrated that SPEM arises, not from professional progenitor cells, but from transdifferentiation of mature Mist1-expressing Chief cells into mucous cell metaplasia. All of these results support the concept that loss of parietal cells from the gastric fundic mucosa induces the development of SPEM from transdifferentiation of Chief cells. Since SPEM appears to be the initial pre-cancerous metaplastic response to oxyntic atrophy, it is critical to understand how transdifferentiation of Chief cells leads to the emergence of SPEM as the central initial event required for the development of dysplasia and neoplasia in the stomach. During the past funding period, we have established that transdifferentiation of Chief cells into SPEM requires an ordered series of cellular events that mediate the downscaling of zymogen granules through autophagy and upscaling of mucous granule production to achieve mucous metaplasia. We have identified discrete interventions that can arrest the process of transdifferentiation through inhibition of the xCT cystine transporter or inhibition of autophagy. We have hypothesized that discrete events mediated by the 14-3-3 protein Stratifin or alterations in miR-148a are critical early triggers for initiating transdifferentiation of Chief cells after severe gastric injury. We will therefore continue our studies of the origin of metaplasia through the prosecution of two specific aims:!!First, we will examine the role of Stratifin in the initiation of reprogramming of chief cells during transdifferentiation into metaplasia. We will seek to evaluate if loss of Stratifin alters the course of transdifferentiation. In addition, we will identify the intracellular phosphoproteins in Chief cells that are targets for Stratifin action. Second, we will determine how miR-148a regulates the initiation and progression of transdifferentiation. We have identified miR-148a as the major miRNA expressed in Chief cells and determined that its expression is rapidly down-regulated at the initiation of transdifferentiation. We will examine the impact of loss of miR-148a on the expression of transcripts and proteins that may mediate transdifferentiation. Validation studies of putative regulators will place these mediators in the context of the discrete steps required for completion of transdifferentiation. ! All of these studies will help identify fundamental mechanisms involved in Chief cell transdifferentiation and may lead to insights in how pre-neoplastic metaplastic lineage changes can be prevented or reversed. !