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: 8835727
• 负责人: Christine Pope Petersen
• 金额: $ 2.71万
• 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/8835727
• 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; 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; public health relevance; 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）：人胃腺癌是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而来的。我们的实验室证明，小鼠胃底的化生并非由位于腺体上颈部区域的专业祖细胞产生，而是由成熟主细胞转分化为表达解痉多肽的化生（SPEM）而发展。这些研究导致胃肿瘤起源概念发生重大范式转变，表明肿瘤前谱系并非源自专业驻留粘膜祖细胞群，而是由成熟酶原细胞谱系的转分化发展而来。此外，多项研究现在表明，在炎症环境下，SPEM 会增加增殖和增加肠化基因表达水平，并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 向肠化和不典型增生进展的精确介质仍然未知。因此，我假设离散的内在粘膜和巨噬细胞衍生因子不仅调节进化，而且调节 SPEM 向更多增殖性、肿瘤前化生的进展。为了解决这个假设，我将追求两个具体目标：首先，我将通过分离巨噬细胞进行 RNA 测序分析来检查与小鼠胃化生进化和进展相关的巨噬细胞的特征。其次，我将使用分离的巨噬细胞和新型 ImSPEM 细胞系，从机制上研究巨噬细胞如何影响体外化生的进展。总体而言，目前的研究重点是可能驱动胃化生到肿瘤前期的炎症细胞机制。