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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：
9278155
负责人：
JAMES Richard GOLDENRING
金额：
$ 34.33万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
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 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9278155
关键词：
Acute Address Adenocarcinoma Antral Atrophic Cancer Etiology 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 Infiltrate Intestinal Intraepithelial Neoplasia Intestinal Metaplasia Intestines Investigation KRAS2 gene Lead Lesion Malignant Neoplasms Mediator of activation protein Metaplasia Metaplastic Modeling Mucous body substance Mus Neck Neoplasms Neoplastic Processes Pathway interactions Patients Phenotype Population Premalignant Process Risk Rodent Model Role Smooth Pursuit South America Stem cells Stomach Work cancer type gastric fundus improved inducible gene expression 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

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 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.

描述（由申请人提供）：人类胃腺癌在幽门螺杆菌诱导的氧合性萎缩和慢性粘膜细胞化生的环境中发展。我们最近的谱系图谱研究表明，小鼠胃底的化生不是由位于腺体上颈部的专业祖细胞产生的，而是由成熟的主细胞转分化发展为Spasmolytic Polypeptide expressed metaplasia （SPEM）。这些研究导致了胃肿瘤起源概念的重大范式转变，表明肿瘤前谱系不是来自专业的常驻粘膜祖细胞群，而是来自成熟的酶原细胞谱系的转分化。此外，多项研究表明，在炎症的影响下，SPEM可以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。我们最近的研究表明，巨噬细胞负责促进增殖性SPEM的进展，但负责SPEM向肠化和不典型增生进展的确切介质尚不清楚。因此，我们假设，离散的内在粘膜和巨噬细胞衍生的因子不仅调节了SPEM的进化，而且还调节了SPEM向增殖性更强的肿瘤前化生的进展。为了解决这一假设，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中的作用。其次，我们将在一个由活化的K-Ras在主细胞中诱导表达驱动的新型化生模型中，评估Ras激活在主细胞转分化SPEM进化中的作用，以及SPEM谱系的进一步肠化。虽然我们之前的研究主要集中在通过主细胞的转分化建立一种新的化生途径，但目前的研究现在集中在这一途径上