Mechanisms underlying gastric intestinal metaplasia and carcinogenesis

胃肠化生和癌变的机制

• 批准号: 10707301
• 负责人: MARCIA Roxana CRUZ-CORREA
• 金额: $ 89.99万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707301
• 关键词: 3-Dimensional; Address; Alcohols; American Cancer Society; Asian; Autologous; Barrett Esophagus; Bile Acids; Bile Reflux; Biological Models; Biopsy; Black Populations; CDX2 gene; Carcinoma; Cells; ChIP-seq; Chromatin; Coculture Techniques; Cues; Development; Diagnosis; Dietary Factors; Dysplasia; Early Diagnosis; East Asian; Epigenetic Process; Epithelial Cells; Epithelium; Esophagogastric Junction; Esophagus; Ethnic Origin; Ethnic Population; Fibroblasts; Fostering; Fundus; Gastric Adenocarcinoma; Gastric mucosa; Gene Expression; Gene Mutation; Genetic; Genetic Transcription; Goals; Helicobacter Infections; High Prevalence; Hispanic Populations; Human; Immune; Incidence; Individual; Inflammation; Inflammatory; Institution; Intestinal Intraepithelial Neoplasia; Intestinal Metaplasia; Intestinal Mucosa; Intestines; Malignant Neoplasms; Mediating; Metaplasia; Molecular; Mus; Mutation; Neoplasms; New York City; Not Hispanic or Latino; Organ; Organoids; Outcome; Pacific Islander; Pathogenesis; Pathway interactions; Patients; Pediatric Hospitals; Peripheral Blood Mononuclear Cell; Play; Population Heterogeneity; Prevention; Process; Property; Puerto Rico; Pyloric antrum; Reporting; Repression; Resolution; Role; SOX21 gene; Sampling; Stomach; TP53 gene; Testing; Tissue Model; Transcriptional Regulation; Tumor Suppressor Genes; Universities; Upper digestive tract structure; cancer diagnosis; cancer survival; carcinogenesis; carcinogenicity; cigarette smoking; ethnic difference; gastric carcinogenesis; gastric intestinal metaplasia; health care disparity; human data; human model; induced pluripotent stem cell; innovation; insight; loss of function; malignant stomach neoplasm; microorganism; mortality; mouse model; novel; prevent; programs; racial difference; racial population; risk stratification; salt intake; screening; single-cell RNA sequencing; spasmolytic polypeptide; stem cell model; stomach cardia; transcription factor; treatment strategy

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.

程序摘要 胃癌或GC（包括胃食管连接癌）是最常诊断的第五次 全球癌症。据报道胃癌发病率和死亡率的显着差异 种族/族裔。在美国，非西班牙裔黑人（NHB），西班牙裔（USH）和非西班牙裔亚洲人或 太平洋岛民（NHAPI）更常见于胃癌，比较死亡率更高 非西班牙裔白人（NHW）。肠上皮（IM）是GC的关键前体，具有中间阶段 发育不良。胃IM倾向于存在于Antrum-Corpus结，尤其是在Incisura angularis上。 胃IM也可以在Cardia中出现。有助于胃IM发展的因素包括胆汁反射x 吸烟，酒精，高盐摄入量和幽门螺杆菌感染。胃和胃中的一个标志 食道（= Barrett的食道）是将细胞身份变为柱状肠道上皮的类型， 表明IM在这两个器官中具有共同的机制。 CDX2等几个关键转录因子 在功能上需要启动IM，也许与其他因素一致，并涉及表观遗传 重新编程。我们提出的研究的主要目标是解决该领域的基本差距（1） 胃im出现了吗？ （2）在胃心脏和胃口中是否有共同的分子途径？ （3） TP53肿瘤抑制基因突变和炎症提示如何促进IM的倡议？ 我们将采用完整的创新平台诱导多能干细胞（IPSC）模型，3D 来自胃IM患者的类器官，以及这些类器官与成纤维细胞和免疫细胞的共同培养 破译微环境线索如何催化从化生质量到异常增生和GEJ/胃的过渡 腺癌。我们试图了解种族如何在胃IM的发病机理中发挥作用 可能会揭示新的见解并通过我们的多机构财团来解决医疗保健分布 （辛辛那提儿童医院，哥伦比亚大学和波多黎各大学）。我们将检验假设 这种细胞自主和非电池自主机制是胃IM，发育不良和 通过以下相互关联的特定目的癌：目标1：确定分子基础 使用诱导多能干细胞（IPSC）的胃IM；目标2。阐明TP53突变和 炎症提示有助于IM和/或发展障碍和癌症的倡议。 基因表达，转录调控和染色质可及性的表征对于 确定预防和/或治疗胃IM/发育不良的推定靶标。