Oxyntic Atrophy and Novel Gastric Lineages

胃酸萎缩和新的胃谱系

• 批准号: 8696796
• 负责人: JAMES Richard GOLDENRING
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696796
• 关键词: Accounting; Acids; Acute; Animals; Antral; Atrophic; Atrophic Gastritis; Cancer Etiology; Cancerous; Cell Culture Techniques; Cell Differentiation process; Cell physiology; Cell surface; Cells; Cessation of life; Chief Cell; Chronic; Developing Countries; Development; Disease; Dysplasia; Epithelial; Epithelium; Event; Evolution; Foveolar Hyperplasia; Funding; Gastric Adenocarcinoma; Gastric Glands; Gastric Parietal Cells; Gastric mucosa; Gastritis; Genes; Goblet Cells; Helicobacter; Helicobacter Infections; Helicobacter pylori; Human; Human Resources; In Vitro; Infection; Inflammation; Inflammatory Response; Injury; Intestinal Metaplasia; Intestines; Intrinsic factor; Investigation; Lead; Lesion; Life; Light; Malignant Neoplasms; Maps; Metaplasia; Metaplastic; Microarray Analysis; Military Personnel; Modeling; Morbidity - disease rate; Mucins; Mucous Membrane; Mucous body substance; Mus; Neoplasms; Pathway interactions; Pepsinogens; Population; Process; Property; Reflux; Regulation; Rodent; Role; Smooth Pursuit; Stem cells; Stomach; Veterans; base; carcinogenesis; gastric fundus; immortalized cell; insight; malignant stomach neoplasm; mouse model; novel; progenitor; response; response to injury; spasmolytic polypeptide; stomach body; transcription factor; transdifferentiation

DESCRIPTION (provided by applicant): Gastric adenocarcinoma remains the second 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. The normal gastric fundic mucosa is assembled from a heterogeneous group of epithelial lineages responsible for the normal secretion of mucins, pepsinogen and HCl. 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 10 years, we have investigated the factors that lead to the development of SPEM in the face of oxyntic atrophy. Using a parietal cell directed protonophore, DMP-777, that induces acute loss of parietal cells, we have defined the dynamics of the induction of SPEM in rodents in the response to acute loss of parietal cells. Our recent lineage mapping studies in mice 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 hypotheses that loss of parietal cells from the gastric fundic mucosa induces the development of SPEM from transdifferentiation of chief cells and that intrinsic mucosal factors regulate the emergence of SPEM as the central step for initiation of gastric neoplasia. Thus, it is essential to understand the factors that elicit and control the emergence of SPEM as the critical initial event required for the development of gastric neoplasia. We will continue our studies of the origin of metaplasia through the prosecution of two specific aims: First, although our lineage mapping studies have determined that chief cells are giving rise to SPEM, suggesting that mature chief cells in general have the capacity to transdifferentiate into metaplasia. Nevertheless, it remains possible that subpopulations of chief cells exist that are the true cryptic progenitor cells for metaplasia. Therefore, we will seek to determine whether subpopulations of chief cells are responsible for development of SPEM by examining whether long- lived chief cell subpopulations may exist as putative quiescent progenitor cells. Furthermore, we will examine whether Lgr5-expressing chief cells in the gastric fundus may represent a quiescent progenitor cell population that could contribute to the development of SPEM. Second, we will seek to identify factors that may influence chief cell transdifferentiation into SPEM in vitro using novel conditionally immortalized cell culture models for mouse chief cells (ImChief) that we have developed during the previous funding period. In ImChief cells, we will determine whether over-expression of the chief cell differentiation-specific transcription factor Mist1 can promote further maturation of chief cell properties. In addition, we will determine whether loss of Mist1 promotes the development of metaplasia following induction of acute parietal cell loss in Mist1 KO mice and in targeted knockdown of Mist1 expression in ImChief cells. Finally, we will examine whether putative regulators of metaplastic transition, identified in our recent gene microarray analysis of mouse SPEM models, may promote chief cell transdifferentiation into SPEM when expressed in ImChief cells.))Through these studies we will gain fundamental insights into the cellular processes that lead to the induction of metaplasia as the critical initiating step for gastric carcinogenesis. )

描述（由申请人提供）： 胃腺癌仍然是全球与癌症相关死亡的第二大最常见原因。在慢性萎缩性胃炎的情况下，绝大多数胃癌通常与幽门螺杆菌感染有关。虽然幽门螺杆菌作为胃癌作用的直接原因的作用已经很好地确立，但谱系变化的细胞基础导致产生前肿瘤的变质和发展为癌症的发展尚不清楚。正常的胃基础粘膜是由一组粘蛋白，胃蛋白酶原和HCL正常分泌的上皮谱系组装的。与幽门螺杆菌感染相关的慢性损伤会导致胃上皮菌组成的显着变化，而角质细胞损失（氧萎缩），表面细胞的扩展（Foveolar增生）和粘液细胞的扩张。现在，在人类的羟基萎缩的情况下，确认了两种化生谱系：肠道化生（以胃粘膜中存在肠内窝状细胞的存在）和痉挛性多肽表达上皮质（SPEM； SPEM；通过在体内的粘液型粘液细胞中表征体内的粘液型细胞）。然而，小鼠的旋律感染仅导致SPEM。在过去的10年中，我们研究了导致催产萎缩时SPEM发展的因素。使用顶壁细胞定向质子团DMP-777，该DMP-777诱导顶叶细胞的急性丧失，我们定义了啮齿动物中SPEM诱导的动力学，以响应顶叶细胞的急性丧失。我们最近在小鼠中的谱系映射研究表明，SPEM不是来自专业祖细胞，而是由表达成熟MIST1的主要细胞转变为粘液细胞化学症。所有这些结果都支持了以下假设：胃基础粘膜中的顶壁细胞丧失诱导了由主要细胞转分化的SPEM的发展，并且内在粘膜因子调节SPEM作为胃肿瘤的核心步骤。因此，必须了解引起和控制SPEM作为胃肿瘤发展所需的关键初始事件的因素。我们将通过起诉两个特定目的来继续研究化生的起源：首先，尽管我们的谱系映射研究已经确定主要细胞正在引起SPEM，这表明一般而言，成熟的主要细胞具有将分化为化学的能力。然而，仍然存在主要细胞的亚群，这是真正的隐性祖细胞用于化学的细胞。因此，我们将寻求确定主要细胞的亚群是否是通过检查长期存在的主要细胞亚群来发展SPEM的原因，这可能是假定的静态祖细胞。此外，我们将检查胃底表达LGR5的主要细胞是否代表可能有助于SPEM发展的静态祖细胞群。其次，我们将寻求使用我们在上一个资金期间开发的小鼠主要细胞（IMCHIEF）的新型有条件永生的细胞培养模型（IMCHIEF）的新型细胞在体外影响主要细胞的因素。在Imchief细胞中，我们将确定主要细胞分化特异性转录因子MISS1的过表达是否可以促进主要细胞特性的进一步成熟。此外，我们将确定Mist1的损失是否会促进Mist1 KO小鼠急性顶壁细胞损失以及Imchief细胞中MIST1表达的靶向敲低后，是否会促进化生的发展。 Finally, we will examine whether putative regulators of metaplastic transition, identified in our recent gene microarray analysis of mouse SPEM models, may promote chief cell tr​​ansdifferentiation into SPEM when expressed in ImChief cells.))Through these studies we will gain fundamental insights into the cellular processes that lead to the induction of metaplasia as the critical initiating step for gastric carcinogenesis. ）