Oxyntic Atrophy and Novel Gastric Lineages

胃腺癌仍然是全球癌症相关死亡的第三大常见原因。浩瀚无边 大多数胃癌在慢性萎缩性胃炎的背景下发生在胃中，通常在 与幽门螺杆菌感染的关系。而幽门螺杆菌作为胃病的直接原因 癌症的发生是公认的，是导致癌症发生的谱系变化的细胞基础。 癌前化生和向癌症的进展仍不清楚。幽门螺杆菌引起的慢性损伤 感染导致胃上皮细胞成分显著改变，壁细胞丢失。 (氧合萎缩)、表面细胞扩张(小凹增生)和粘液细胞化生。二 化生谱系现在被认为是人类氧化性萎缩的背景：肠化生 (以胃粘膜中存在肠杯状细胞为特征)和解痉多肽 表达化生(SPEM；特征是体内存在胃窦型粘液细胞 胃)。然而，小鼠体内的幽门螺杆菌感染只会导致SPEM。在过去的20年里，我们已经 探讨了在氧合萎缩的情况下，导致SPEM发生的因素。使用血统- 在小鼠的图谱研究中，我们已经证明了SPEM不是来自专业的祖细胞，而是 从表达Mist1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丧失导致胃溃疡发生的观点。 SPEM来源于主细胞的转分化。因为SPEM似乎是最初的癌前化生 对于氧合萎缩的反应，了解主细胞的转分化是如何导致 SPEM的出现是异型增生和肿瘤发生所必需的中心初始事件 胃。在过去的资助期间，我们已经建立了主细胞转分化为 SPEM需要一系列有序的细胞事件，通过 自噬和粘液颗粒产生的放大以实现粘液化生。我们已经确定了 可通过抑制XCT半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调停的离散事件 蛋白Stratifin或miR-148A的改变是启动Head转分化的关键早期触发因素 严重胃损伤后的细胞。因此，我们将继续研究化生的起源，通过 检控的两个具体目标：首先，我们会研究Stratifin在启动重新编排程序方面的角色 转分化为化生过程中的主要细胞。我们将寻求评估Stratifin的损失是否会改变 转分化过程。此外，我们将在主要细胞中鉴定细胞内磷酸蛋白， 是Stratifin行动的目标。其次，我们将确定miR-148A如何调节启动和 转分化的进展。我们已经确定miR-148A是在主细胞中表达的主要miRNA 并确定其表达在转分化开始时迅速下调。我们会 检测miR-148A缺失对转录本和可能介导的蛋白质表达的影响 转分化。对假定的监管机构的验证研究将把这些调解人放在 完成转分化所需的离散步骤。好了！ 所有这些研究都将有助于确定主要细胞转分化和 可能导致对如何预防或逆转肿瘤前化生谱系变化的见解。 好了！

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. !