Induction and Evolution of Metaplasia in the Stomach

胃化生的诱导和进化

• 批准号: 9916731
• 负责人: JAMES Richard GOLDENRING
• 金额: $ 47.26万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916731
• 关键词: Ablation; Acids; Acute; Address; Antral; Atrophic; Atrophic Gastritis; Cell Line; Cell Lineage; Cells; Characteristics; Chemosensitization; Chief Cell; Chronic; Development; Epithelial; Epithelial Cells; Epithelium; Event; Evolution; Gastric Metaplasia; Gastric Parietal Cells; Gastric mucosa; Gland; Goblet Cells; Helicobacter pylori; Human; Immune; Immunologic Factors; Inflammation; Injury; Interleukin-13; Intestinal Metaplasia; Intestines; Investigation; Left; Mediating; Mediator of activation protein; Metaplasia; Mucous Membrane; Mucous body substance; Mucus-Secreting Cell; Mus; Organoids; Phenotype; Physiological; Population; Process; Proteins; Regulation; Role; Side; Signal Transduction; Smooth Pursuit; Stomach; System; autocrine; chronic infection; cytokine; insight; macrophage; malignant stomach neoplasm; neoplastic; premalignant; prevent; repaired; response; spasmolytic polypeptide; transdifferentiation

Atrophic gastritis (parietal cell loss or oxyntic atrophy) is considered the most common precursor to gastric cancer in humans. Chronic infection with Helicobacter pylori represents the most common cause of atrophy. In the stomach, metaplasia arises following parietal cell loss. Two types of metaplasia occur in he human stomach: intestinal metaplasia (the presence of intestinal goblet cell lineages in the stomach) and Spasmolytic Polypeptide-Expressing Metaplasia or SPEM (the presence of deep antral gland type mucus cells in the stomach corpus). Investigations over the past decade have led to the recognition that SPEM lineages are substantially derived from transdifferentiation of protein-secreting chief cells into mucus-secreting metaplastic lineages. SPEM represents an initial metaplastic response to acute injuries in the stomach. However, progression of SPEM to more intestinalized and proliferative lineages requires the influence of M2- macrophages. With chronic inflammation in the stomach, SPEM appears to evolve into intestinal metaplasia. Our recent investigations have also determined that activation of Ras is critical at all stages of metaplasia evolution from initial transdifferentiation of SPEM, to promotion of proliferative SPEM, and to emergence of intestinal metaplasia. Thus, critical extrinsic immune factors and intrinsic epithelial Ras signaling combine to promote the evolution and expansion of metaplasia in the stomach. We have therefore hypothesized that immune cell populations drive both the induction of SPEM and the progression of metaplasia. To evaluate this hypothesis, we will examine two specific aims: First, we will examine the role of intrinsic immune cells (ILC2s) in the gastric mucosa on the induction of metaplasia. Our previous investigations have implicated a cascade of IL-33 to IL-13 in the induction of metaplasia in the corpus of the stomach. Since intrinsic immune ILC2s are thought to represent the major population of cells responsible for secretion of IL-13, we will seek to characterize the diversity of ILC2s in the stomach and their response to parietal cell loss. We will examine whether ablation of ILC2s prevents the induction of metaplasia following acute oxyntic atrophy. Finally we will examine whether IL-13 is a direct activator of transdifferentiation in chief cells. Second, will identify the immune cell derived factors and intrinsic autocrine epithelial signals that can promote progression of metaplasia to a more intestinalized and proliferative phenotype. While transdifferentiation of chief cells into SPEM is an initial transition triggered as a response to parietal cell loss, further progression to more proliferative and intestinalized metaplasia requires other influences. We have developed metaplastic gastroid lines from Mist1-KRas mice 1 month or 4 months after induction of active Ras, which display the characteristics of either SPEM or intestinal metaplasia, respectively. We will utilize these cells to evaluate whether immune or autocrine regulators can influence SPEM to progress towards intestinal metaplasia. These investigations will define more precisely the dynamic regulators of the induction and progression of metaplasia in the stomach.

萎缩性胃炎（壁细胞丧失或泌酸性萎缩）被认为是胃溃疡最常见的前兆。 人类的癌症幽门螺杆菌的慢性感染是萎缩的最常见原因。在 在胃中，壁细胞丧失后出现化生。在人类中有两种类型的化生 胃：肠上皮化生（胃中存在肠杯状细胞谱系）和痉挛 表达多肽的化生或SPEM（在胃窦部中存在深窦腺型粘液细胞） 胃体）。过去十年的研究已经认识到SPEM谱系是 实质上来源于蛋白分泌主细胞向粘液分泌化生细胞的转分化 血统SPEM代表胃急性损伤的初始化生反应。然而，在这方面， SPEM向更趋分化和增殖的谱系的进展需要M2的影响。 巨噬细胞随着胃的慢性炎症，SPEM似乎演变成肠上皮化生。 我们最近的研究也确定Ras的激活在化生的所有阶段都是至关重要的 从SPEM的初始转分化到增殖SPEM的促进和SPEM的出现， 肠上皮化生因此，关键的外源性免疫因子和内源性上皮细胞Ras信号传导联合收割机结合， 促进胃内化生的发展和扩大。因此，我们假设， 免疫细胞群驱动SPEM的诱导和化生的进展。评价这一 假设，我们将研究两个具体目标：首先，我们将研究内在免疫细胞（ILC 2）的作用。 在胃粘膜上诱导化生。我们之前的调查显示 IL-33至IL-13在胃体化生诱导中的作用由于内在免疫ILC 2是 被认为代表了负责分泌IL-13的主要细胞群，我们将寻求 描述胃中ILC 2的多样性及其对壁细胞损失的反应。我们将研究 ILC 2的消融是否防止急性泌酸性萎缩后化生的诱导。最后我们将 检查IL-13是否是主细胞转分化的直接激活剂。第二，将识别 免疫细胞衍生因子和内源性自分泌上皮信号，可以促进进展， 化生为更增殖化和增殖表型。当主细胞转分化为 SPEM是对壁细胞损失的反应而触发的初始过渡，进一步发展为更多 增殖性和非增殖性化生需要其他影响。我们发现了化生性胃腺炎 在诱导活性Ras后1个月或4个月，来自Mist 1-KRas小鼠的细胞系显示出以下特征： 分别为SPEM或肠化生。我们将利用这些细胞来评估是否免疫或 自分泌调节剂可以影响SPEM向肠上皮化生的进展。这些调查将 更精确地定义胃化生的诱导和进展的动态调节因子。