Mechanisms underlying gastric intestinal metaplasia and carcinogenesis

胃肠化生和癌变的机制

基本信息

项目摘要

PROGRAM SUMMARY Gastric cancer or GC (inclusive of gastroesophageal junction cancers) is the 5th most frequently diagnosed cancer globally. Significant variability in gastric cancer incidence and mortality has been reported between racial/ethnic groups. In the U.S., non-Hispanic Blacks (NHB), Hispanics (USH), and non-Hispanic Asian or Pacific Islander (NHAPI) are more commonly diagnosed with gastric cancer and have higher mortality compared to Non-Hispanic Whites (NHW). Intestinal metaplasia (IM) is a key precursor to GC with an intermediate stage of dysplasia. Gastric IM tends to be present at the antrum-corpus junction, particularly at the incisura angularis; gastric IM can also arise in the cardia. Factors that contribute to the development of gastric IM include bile reflux cigarette-smoking, alcohol, high salt intake, and H. pylori infection. A hallmark of IM in both the stomach and the esophagus (=Barrett’s esophagus) is the change of cellular identity to a columnar intestinal type of epithelium, suggesting that IM has shared mechanisms across these two organs. Several key transcription factors like CDX2 are functionally required to initiate IM, perhaps in concert with other factors and involving epigenetic reprogramming. The main goal of our proposed studies is to resolve fundamental gaps in the field (1) How does gastric IM arise? (2) Is there a common molecular pathway initiating IM in the gastric cardia and antrum? (3) How do TP53 tumor suppressor gene mutations and inflammatory cues each contribute to the initiation of IM? We will employ complementary, innovative platforms inducible pluripotent stem cells (iPSC) models, 3D organoids from patients with gastric IM, and co-culture of these organoids with fibroblasts and immune cells to decipher how microenvironmental cues catalyze the transition from metaplasia to dysplasia and GEJ/gastric adenocarcinoma. We seek to understand how ethnicity may play a role in the pathogenesis of gastric IM as that might reveal new insights and address health care disparities through our multi-institutional consortium (Cincinnati Children’s Hospital, Columbia University, and University of Puerto Rico). We will test the hypothesis that cell autonomous and non-cell autonomous mechanisms underlie the formation of gastric IM, dysplasia, and carcinoma through the following interrelated Specific Aims: Aim 1: To identify the molecular basis of gastric IM using inducible pluripotent stem cells (iPSC); Aim 2. To elucidate how TP53 mutations and inflammatory cues contribute to the initiation of IM and/or the progression to dysplasia and cancer. Characterization of gene expression, transcriptional regulation, and chromatin accessibility will be invaluable to identify putative targets to prevent and/or treat gastric IM/dysplasia.

项目成果

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MARCIA Roxana CRUZ-CORREA其他文献

MARCIA Roxana CRUZ-CORREA的其他文献

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{{ truncateString('MARCIA Roxana CRUZ-CORREA', 18)}}的其他基金

Mechanisms underlying gastric intestinal metaplasia and carcinogenesis
胃肠化生和癌变的机制
  • 批准号:
    10707301
  • 财政年份:
    2022
  • 资助金额:
    $ 95.06万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10417253
  • 财政年份:
    2020
  • 资助金额:
    $ 95.06万
  • 项目类别:
Hispanic Alliance for Clinical and Translational Research (Alliance)
西班牙裔临床和转化研究联盟(联盟)
  • 批准号:
    10372243
  • 财政年份:
    2020
  • 资助金额:
    $ 95.06万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10654584
  • 财政年份:
    2020
  • 资助金额:
    $ 95.06万
  • 项目类别:
Hispanic Alliance for Clinical and Translational Research (Alliance)
西班牙裔临床和转化研究联盟(联盟)
  • 批准号:
    10027567
  • 财政年份:
    2020
  • 资助金额:
    $ 95.06万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10252022
  • 财政年份:
    2020
  • 资助金额:
    $ 95.06万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10027568
  • 财政年份:
    2020
  • 资助金额:
    $ 95.06万
  • 项目类别:
Channeling the voice of underserved communities on nutritional insufficiency and unaddressed needs on maternal infant health.
传达服务不足社区关于营养不足和母婴健康需求未得到解决的声音。
  • 批准号:
    10395287
  • 财政年份:
    2020
  • 资助金额:
    $ 95.06万
  • 项目类别:
Hispanic Alliance for Clinical and Translational Research (Alliance)
西班牙裔临床和转化研究联盟(联盟)
  • 批准号:
    10252021
  • 财政年份:
    2020
  • 资助金额:
    $ 95.06万
  • 项目类别:
SARS-CoV-2 genomic surveillance across the island of Puerto Rico
波多黎各全岛 SARS-CoV-2 基因组监测
  • 批准号:
    10381209
  • 财政年份:
    2020
  • 资助金额:
    $ 95.06万
  • 项目类别:

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