Pathways of Injury and Repair in Barrett's Carcinogenesis

计划摘要 该项目的中心假设是“鳞状上皮完整性改变(PRJ 1)和 炎症损伤(Prj 2)激活包括EPHB2(Prj 3)在内的影响前体细胞的信号通路 在鳞状突交界处(SCJ)、食道粘膜下腺(ESMG)和基底部 鳞状生态位，导致调控因子的改变，包括Notch，Myc，p63和 SOX9，导致腺泡导管化生(ADM)、多层上皮(MLE)、Barrett‘s食道 (BE)，最终是食管腺癌(EAC)。我们计划的具体目标是： 1)阐明突变的VSIG10L改变上皮完整性导致MLE和BE的信号通路 就像新的小鼠模型上的化生。 2)明确CXCL8(IL-8)在食道损伤后ESMG中的时空分布规律。 表型ESMG中导致腺泡导管化生(ADM)发展的炎性浸润物 与BE/EAC关联。 3)确定导致c-myc活化和化生细胞分化的EPHB2信号的介体。 损伤后BE的发生发展及其向EAC的进展。 4)确定如何改变上皮完整性、炎症细胞和控制的信号分子的改变 分化(EPHB2)通过改变转录因子导致化生。 5)通过最先进的核心资源为调查人员提供有效支持，将项目整合在一起 生物仓库、生物信息学和行政服务。 这些目标建立在相当多的临床、基础科学和翻译专业知识的基础上并相互配合 可在我们的机构获得，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)然后将实验室发现转化为 用于有效检测、分子风险分层和预防疾病进展的临床应用 去东非。

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.