Induction and Evolution of Metaplasia in the Stomach

胃化生的诱导和进化

• 批准号: 8722082
• 负责人: JAMES Richard GOLDENRING
• 金额: $ 34.08万
• 依托单位: VANDERBILT UNIVERSITY
• 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 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8722082
• 关键词: Acute; Address; Adenocarcinoma; Antral; Atrophic; Cancer Etiology; Cancerous; Cell Line; Cell Lineage; Cells; Cessation of life; Characteristics; Chief Cell; Chronic; Development; Dysplasia; Early Diagnosis; Early treatment; Event; Evolution; Funding; Gastric Parietal Cells; Gene Expression; Generations; Genes; Gerbils; Gland; Goblet Cells; Helicobacter; Helicobacter pylori; Human; Immigrant; Immune; Inflammation; Inflammatory; Intestinal Metaplasia; Intestines; Investigation; Lead; Lesion; Malignant Neoplasms; Maps; Mediator of activation protein; Metaplasia; Metaplastic; Modeling; Mucous body substance; Mus; Neck; Neoplasms; Neoplastic Processes; Pathway interactions; Patients; Phenotype; Population; Process; Risk; Rodent Model; Role; Smooth Pursuit; Stem cells; Stomach; Work; cancer type; gastric fundus; improved; insight; macrophage; malignant stomach neoplasm; mouse model; neoplastic; novel; novel strategies; promoter; public health relevance; screening; spasmolytic polypeptide; therapy development; transdifferentiation

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.

人类胃中的腺癌是在幽门螺杆菌的环境下进化而来的 诱导泌酸萎缩和慢性粘液细胞化生。我们最近的血统 绘图研究表明，小鼠胃底化生确实 不是由位于上颈部区域的专业祖细胞产生的 腺体，而是由成熟主细胞转分化为 解痉多肽表达化生，或 SPEM。这些研究导致了 胃肿瘤起源概念的重大范式转变，表明 肿瘤前谱系并非由专业驻留粘膜祖细胞产生 细胞群，而是由成熟酶原细胞的转分化发展而来 血统。此外，多项研究现在表明，SPEM 在 炎症，可以增加增殖和增加水平 肠化基因表达，并在人类中产生杯状细胞肠 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，但精确的 负责 SPEM 向肠化进展的介质和 发育异常仍未知。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，还调节巨噬细胞的进展 SPEM 检测更多增殖性癌前化生。为了解决这个假设，我们 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。其次，我们来评估Ras的作用 SPEM从转分化主细胞进化过程中的激活以及进一步 诱导型驱动的新型化生模型中 SPEM 谱系的肠化 主细胞中激活的 K-Ras 的表达。虽然我们之前的调查已经 专注于建立一条新的化生生成途径 主细胞的转分化，目前的研究重点是 可能驱动化生为癌前病变的机制。