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）：人胃腺癌在幽门螺杆菌诱导的泌酸萎缩和慢性粘液细胞化生的背景下演变。我们的实验室证明，小鼠胃底化生不是由位于腺体上颈部的专职祖细胞引起的，而是由成熟主细胞转分化为痉挛性多肽表达化生（SPEM）。这些研究已经导致了一个显着的范式转变的概念，胃肿瘤的起源，这表明，肿瘤前谱系不产生专业居民粘膜祖细胞群体，而是从成熟的酶原细胞谱系的转分化。此外，现在多项研究表明，SPEM在炎症环境中产生增殖增加和增殖基因表达水平增加，并且在人类中引起杯状细胞肠化生。我最近的研究表明，巨噬细胞负责促进增殖性SPEM进展，但负责SPEM向增殖和发育不良进展的精确介质仍然未知。因此，我推测，离散的内在粘膜和巨噬细胞源性因子调节不仅演变，而且进展的SPEM更多的增殖，癌前化生。为了解决这一假设，我将追求两个具体的目标：首先，我将检查与小鼠胃化生的演变和进展相关的巨噬细胞的特征，通过分离巨噬细胞进行RNA测序分析。其次，使用分离的巨噬细胞和一种新的ImSPEM细胞系，我将研究巨噬细胞如何影响体外化生的进展。总体而言，目前的调查集中在炎症细胞机制，可能会推动化生癌前病变的胃。