Inflammatory mediators promote the development of metaplasia in the stomach

炎症介质促进胃化生的发展

• 批准号: 8927344
• 负责人: Christine Pope Petersen
• 金额: $ 2.75万
• 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: 2014-09-15 至 2016-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8927344
• 关键词: Acute; Address; Adenocarcinoma; Antral; Atrophic; Biological Models; Cancer Etiology; Cancerous; Cell Line; Cell Lineage; Cells; Cessation of life; Characteristics; Chief Cell; Chronic; Development; Dysplasia; Early Diagnosis; Early treatment; Event; Evolution; Gastric Parietal Cells; Gene Expression; Generations; Genes; Gerbils; Gland; Goblet Cells; Health; Helicobacter; Helicobacter pylori; Human; Immigrant; Immune; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Intestinal Metaplasia; Intestines; Investigation; Laboratories; Lead; Lesion; Malignant Neoplasms; Maps; Mediator of activation protein; Metaplasia; Metaplastic; Mucous body substance; Mus; Neck; Neoplasms; Neoplastic Processes; Pathway interactions; Patients; Phenotype; Population; Process; RNA Sequence Analysis; Risk; Rodent Model; Role; Smooth Pursuit; Stem cells; Stomach; Work; cancer type; gastric fundus; improved; in vivo; insight; macrophage; malignant stomach neoplasm; mouse model; neoplastic; novel; novel strategies; promoter; screening; skills; spasmolytic polypeptide; therapy development; transdifferentiation

DESCRIPTION (provided by applicant): Adenocarcinoma in the human stomach evolves in the setting of Helicobacter pylori-induced oxyntic atrophy and chronic mucous cell metaplasia. Our lab 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 develops both increased proliferation and increasing levels of intestinalizing gene expression in the setting of inflammation, and in humans gives rise to goblet cell intestinal metaplasia. My 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. I 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, I will pursue two specific aims: First, I will examine the characteristics of macrophages associated with the evolution and progression of metaplasia in the mouse stomach by isolating macrophages for RNA sequencing analysis. Second, using isolated macrophages and a novel ImSPEM cell line, I will examine mechanistically how macrophages influence the progression of metaplasia in vitro. Overall, the present investigations focus on the inflammatory cell mechanisms that might drive metaplasias to preneoplasia in the stomach.

描述（由申请人提供）：在人类胃中的腺癌在幽门螺杆菌诱导的催产萎缩和慢性粘液细胞化生的情况下演变。我们的实验室表明，小鼠胃底的化生不是来自位于腺体上颈部区域的专业祖细胞引起的，而是从成熟的主要细胞转变为痉挛性多肽的转变，表达了化生或SPEM。这些研究导致了胃肿瘤起源的概念的显着范式转移，这表明前塑性谱系并非是由专业居民粘膜祖细胞群体引起的，而是由于成熟的Zymogenic细胞谱系的转分化而发展。此外，现在的多项研究表明，SPEM在炎症的环境中既增加增殖和肠道基因表达水平的增加，并且在人类中会导致杯状细胞肠道化生。我最近的研究表明，巨噬细胞是促进增生性SPEM进展的原因，但是导致SPEM向肠道化和发育不良的促进的确切介体仍然未知。因此，我假设离散的内在粘膜和巨噬细胞衍生的因素不仅调节了进化，而且还调节了SPEM向更加增殖的，肿瘤性塑性化的变化的进展。为了解决这一假设，我将追求两个具体的目的：首先，我将通过分离巨噬细胞进行RNA测序分析来研究与小鼠胃中的变化和进展相关的巨噬细胞的特征。其次，使用孤立的巨噬细胞和新型的IMSPEM细胞系，我将从机械上检查巨噬细胞如何影响体外变质的进展。总体而言，本研究的重点是炎症细胞机制，这些机制可能会导致胃中肿瘤的质量变质。