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Induction and Evolution of Metaplasia in the Stomach

胃化生的诱导和进化

基本信息

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
项目类别：
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

项目摘要

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.

人类胃腺癌在幽门螺杆菌的背景下发展