Pathways of Injury and Repair in Barrett's Carcinogenesis

巴雷特癌发生过程中的损伤和修复途径

基本信息

批准号：
10713938
负责人：
AMITABH CHAK
金额：
$ 226.89万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-20 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10713938
关键词：
Address Affect Barrett Esophagus Barrett&apos s carcinogenesis Basic Science Bibliometrics Bioinformatics Biological Markers Biology Cell Adhesion Molecules Cell Communication Cell Differentiation process Cells Clinical Collaborations Complex Detection Development Devices Disease Duct (organ) structure Dysplasia EPHB2 gene Epithelial Cell Junction Epithelium Esophageal Adenocarcinoma Esophageal injury Esophagus Genes Genetic Genetic Predisposition to Disease Gland Goals Grant HNF4A gene Hyperactivity IL8 gene Individual Inflammatory Inflammatory Infiltrate Inherited Injury Institution Interdisciplinary Study Laboratories Laboratory Research Laboratory Scientists Lead Legal patent MAPK8 gene Manuscripts Mediating Mediator Metaplasia Molecular Molecular Target Morbidity - disease rate Mutate Pathway interactions Pattern Phenotype Population Predisposition Prevention Prognosis Public Health Publishing Reflux Research Research Personnel Research Project Grants Resources Role Sampling Services Signal Pathway Signal Transduction Signaling Molecule Specialized Program of Research Excellence Squamous Epithelium Submucosa Susceptibility Gene System TGFB1 gene Therapeutic Tissues Translating Translational Research Universities biobank c-myc Genes cancer prevention carcinogenesis carcinogenicity cell growth cell motility clinical application detection method esophageal carcinogenesis fusion gene genetic approach healing improved injury and repair instructor molecular marker mortality mouse model notch protein novel precursor cell prevent professor programs repaired response to injury risk stratification screening support network synergism transcription factor transcriptomics wound healing wound response

项目摘要

PROGRAM SUMMARY The central hypothesis of this program project is that “Altered squamous epithelial integrity (Prj 1) and inflammatory injury (Prj 2) activate signaling pathways including EPHB2 (Prj 3) that affect precursor cells at the squamocolumnar junction (SCj) transition, esophageal submucosal gland (ESMG), and basal squamous niches, resulting in the alteration of regulatory factors that include Notch, Myc, p63, and SOX9, leading to acinar ductal metaplasia (ADM), multi-layered epithelium (MLE), Barrett's esophagus (BE), and ultimately esophageal adenocarcinoma (EAC).” The Specific Aims of our program are: 1) To elucidate signaling pathways by which mutated VSIG10L alters epithelial integrity leading to MLE and BE like metaplasia on novel mouse models. 2) To define the spatial and temporal pattern of CXCL8 (IL-8) in ESMG following esophageal injury and phenotype the inflammatory infiltrate that leads to the development of acinar ductal metaplasia (ADM) in ESMG associated with BE/EAC. 3)To identify mediators of EPHB2 signaling that lead to c-MYC activation and metaplastic cellular differentiation after injury in the development of BE and its progression to EAC. 4) To define how altered epithelial integrity, inflammatory cells, and alteration of signaling molecules that control differentiation (EPHB2) lead to metaplasia by altering transcription factors. 5) Integrate projects by providing investigators effective support through Core resources with state-of-the-art Biorepository, Bioinformatics, and Administrative Services. These objectives build and synergize on the considerable clinical, basic science, and translational expertise available at our institutions, 1) to focus laboratory research on understanding the genetic susceptibility and molecular changes that influence the development of BE and EAC; and 2) to then translate laboratory discoveries into clinical applications for effective detection, molecular risk stratification, and prevention of progression from BE to EAC.

计划概要该计划项目的中心假设是“鳞状上皮完整性改变（Prj 1）和炎症损伤 (Prj 2) 激活信号通路，包括影响前体细胞的 EPHB2 (Prj 3) 鳞柱交界处 (SCj)、食管粘膜下腺 (ESMG) 和基底层鳞状微环境，导致包括 Notch、Myc、p63 和 SOX9，导致腺泡导管化生 (ADM)、多层上皮 (MLE)、巴雷特食管 (BE)，最终食管腺癌 (EAC)。” 1) 阐明突变 VSIG10L 改变上皮完整性导致 MLE 和 BE 的信号通路就像新型小鼠模型上的化生一样。 2) 定义食管损伤后 ESMG 中 CXCL8 (IL-8) 的空间和时间模式 ESMG 中导致腺泡导管化生 (ADM) 发展的炎症浸润表型与 BE/EAC 相关。 3)鉴定导致c-MYC激活和化生细胞分化的EPHB2信号传导介质损伤后发生 BE 及其进展为 EAC。 4) 定义上皮完整性、炎症细胞和控制信号分子的改变是如何改变的分化（EPHB2）通过改变转录因子导致化生。 5) 通过核心资源与最先进的技术为研究者提供有效支持来整合项目生物样本库、生物信息学和行政服务。这些目标建立在大量的临床、基础科学和转化专业知识的基础上并与之相结合我们的机构可以提供这些信息，1) 将实验室研究重点放在了解遗传易感性和影响 BE 和 EAC 发展的分子变化；2) 转化实验室发现进入临床应用以进行有效检测、分子风险分层和预防疾病进展是至 EAC。