Gastroesophageal junction stem cells as the origin of Barretts esophagus and cancer

胃食管连接处干细胞是巴雷特食管和癌症的起源

基本信息

批准号：
10506097
负责人：
Jianwen Que
金额：
$ 97.2万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10506097
关键词：
3-Dimensional ATAC-seq Acceleration Address Adenocarcinoma Affect Automobile Driving Barrett Esophagus Basal Cell Bile Acids Biology Cell physiology Cells Cellular biology Cessation of life Characteristics Chromatin Chronic Clonal Evolution Country DNA Damage Data Development Disease Disease Progression Distal Dysplasia Dysplasia in Barrett&apos s Esophagus Epithelial Attachment Esophageal Adenocarcinoma Esophagitis Esophagogastric Junction Esophagus Evolution Financial Hardship Gastric Adenocarcinoma Gastroesophageal reflux disease Gene Expression Profile Genetic Genetic Determinism Genomics Health Human In Vitro Incidence Inflammation Inflammatory Response Injury Intestines Joints Knowledge Lesion Lymphoid Cell Malignant - descriptor Malignant Neoplasms Malignant neoplasm of esophagus Metaplasia Modeling Molecular Molecular Profiling Mus Mutation Obesity Organoids Pathogenesis Pathway interactions Patients Population Pre-Clinical Model Resistance Risk Risk Factors Role Side Simple Columnar Epithelium Specific qualifier value Stomach TP53 gene Testing Tissues Transitional Epithelium Work cancer type carcinogenesis carcinogenicity cytokine effective therapy epigenomics feeding in vivo innovation insight malignant stomach neoplasm molecular phenotype mouse genetics mouse model mutant novel novel strategies novel therapeutics progenitor response single-cell RNA sequencing stem stem cell differentiation stem cells stem-like cell stomach cardia transcriptome sequencing tumor tumor progression

3-Dimensional ATAC-seq Acceleration Address Adenocarcinoma Affect Automobile Driving Barrett Esophagus Basal Cell Bile Acids Biology Cell physiology Cells Cellular biology Cessation of life Characteristics Chromatin Chronic Clonal Evolution Country DNA Damage Data Development Disease Disease Progression Distal Dysplasia Dysplasia in Barrett&apos s Esophagus Epithelial Attachment Esophageal Adenocarcinoma Esophagitis Esophagogastric Junction Esophagus Evolution Financial Hardship Gastric Adenocarcinoma Gastroesophageal reflux disease Gene Expression Profile Genetic Genetic Determinism Genomics Health Human In Vitro Incidence Inflammation Inflammatory Response Injury Intestines Joints Knowledge Lesion Lymphoid Cell Malignant - descriptor Malignant Neoplasms Malignant neoplasm of esophagus Metaplasia Modeling Molecular Molecular Profiling Mus Mutation Obesity Organoids Pathogenesis Pathway interactions Patients Population Pre-Clinical Model Resistance Risk Risk Factors Role Side Simple Columnar Epithelium Specific qualifier value Stomach TP53 gene Testing Tissues Transitional Epithelium Work cancer type carcinogenesis carcinogenicity cytokine effective therapy epigenomics feeding in vivo innovation insight malignant stomach neoplasm molecular phenotype mouse genetics mouse model mutant novel novel strategies novel therapeutics progenitor response single-cell RNA sequencing stem stem cell differentiation stem cells stem-like cell stomach cardia transcriptome sequencing tumor tumor progression

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项目摘要

Project Summary The rapid increase in the incidence of Barrett’s esophagus (BE), its malignant form esophageal adenocarcinoma (EAC), and junctional gastric cancer has produced serious health and financial burdens in the U.S. Thus far, effective treatment options for these diseases are limited in part due to an incomplete understanding of the molecular mechanisms driving the initial metaplasia and subsequent neoplastic progression. This application, by two PIs with complementary expertise, seeks to address the issue through combining scRNA-sequencing analysis, innovative BE mouse models and organoid modeling. We previously demonstrated that gastric cardia progenitor cells and transitional basal cell (TBCs) contribute to BE in the transitional zone of the gastro-esophageal junction (GEJ). However, how these progenitor cells behave in BE-dysplasia-EAC progression remains unclear. Additionally, the molecular mechanism driving the disease progression is also unknown. Our preliminary data suggest GEJ metaplasia and its progression towards EAC involves progenitor plasticity facilitated by p53 loss, an early genetic lesion in BE. Furthermore, we found that Barrett’s metaplasia and EAC is associated with the enrichment of tuft cells. Therefore we hypothesize that Barrett’s metaplasia and dysplasia originate from GEJ progenitor cells, modulated by the presence of p53 mutation and tuft cell expansion. Three specific aims are formulated to test the hypothesis: Aim 1 is to determine the origins and evolution of BE metaplasia from progenitor cells at the EGJ. Aim 2 is to elucidate the mechanisms by which p53 mutation promotes BE progression, and Aim 3 is to clarify the role of tuft cells in BE pathogenesis and progression. Combining our joint expertise on mouse genetics, cell biology, chromatin biology and epigenomics, this work will provide novel mechanistic insights into the mechanisms underlying Barrett’s metaplasia and its malignant progression, offering new approaches to treat these diseases.

项目摘要巴雷特食管（BE）的发病率迅速增加，其恶性形成食管腺癌（EAC）和连接性胃癌在美国造成了严重的健康和金融燃烧，这些疾病的有效治疗选择受到限制，部分原因是对分子机制驱动初始化生和随后的肿瘤进展。此应用程序，由两个具有完整专业知识的PI，试图通过结合SCRNA测序分析来解决这个问题，创新的是小鼠模型和器官建模。我们以前证明了胃Cardia祖细胞细胞和过渡性鞋底细胞（TBC）有助于处于胃道交界处的过渡区（GEJ）。但是，这些祖细胞在BE-DYSPLASIA-EAC进展中的表现如何尚不清楚。另外，驱动疾病进展的分子机制也未知。我们的初步数据建议GEJ化学及其向EAC的发展涉及p53损失制备的祖细胞可塑性， BE中的早期遗传病变。此外，我们发现Barrett的Metaplasia和EAC与簇细胞的富集。因此，我们假设Barrett的化生和发育不良起源于GEJ 祖细胞，由p53突变和簇细胞膨胀的存在调节。三个具体目标是为了检验假设而制定的：目标1是确定从 EGJ的祖细胞。目标2是阐明p53突变促进的机制进展和目标3是阐明簇细胞在发病和进展中的作用。结合我们的关节小鼠遗传学，细胞生物学，染色质生物学和表观基因组学专业知识将提供新颖对Barrett Metaplasia及其恶性进展的机制的机械洞察力，提供治疗这些疾病的新方法。