Project 1 - Genetic Predisposition To Barrett's Esophagus and Esophageal Adenocarcinoma

项目摘要 Barrett食管（BE）和食管腺癌（EAC）是一种复杂的疾病， 遗传因素我们在一个大家族中成功地发现了VSIG 10 L分离的有害变体。这 是第一个报道的BE和EAC易感基因。VSIG 10 L似乎在粘附中起作用， 复层鳞状上皮的分化/成熟。遗传基础的进一步线索来自我们的 混合物作图研究，该研究已经确定了两个与过量 非裔美国人的欧洲血统。因此，项目1的BETRNet重点是确定以下遗传基础： BE和EAC患病率的种族差异。项目1的第二个BETRNet重点是创建一个基因 基于VSIG 10 L的工程小鼠模型，以了解从鳞状上皮到 化生性巴雷特上皮该项目现在将通过以下方式在这些发现的基础上再接再厉： 1)使用密集SNP基因分型，NextGen测序和ATAC-seq来识别种族不同的遗传 解释BE和EAC患病率种族差异的变异; 2)使用基因工程化的VSIG 10 L敲除和VSIG 10 L S631 G变体携带小鼠， 了解VSIG 10 L如何促进正常鳞状上皮细胞食管炎 化生、异型增生、癌症进展; 项目1的意义首先是将BE和EAC种族差异的临床观察转化为 实验室来确定致病的遗传基础。此外，该项目将建立在我们成功发现 第一个家族性易感性遗传变异，通过了解该基因在化生中的功能， Barrett上皮的转化。

PROJECT SUMMARY Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) are complex diseases with undiscovered genetic factors. We successfully discovered a deleterious variant in VSIG10L segregating in a large family. This is the first such reported gene for susceptibility to BE and EAC. VSIG10L appears to function in adhesion and differentiation/maturation of stratified squamous epithelium. Further clues for a genetic basis comes from our admixture mapping study, which has identified two specific chromosomal regions associated with excess European ancestry in African Americans. The BETRNet focus of Project 1 is thus to identify the genetic basis of racial disparity in the prevalence of BE and EAC. A second BETRNet focus of Project 1 is to create a genetically engineered mouse model based on VSIG10L to understand the transformation from squamous epithelium to metaplastic Barrett's epithelium. This project will now build on these discoveries by: 1) Using dense SNP genotyping, NextGen sequencing, and ATAC-seq to identify racially disparate genetic variants that explain racial differences in prevalence of BE and EAC; 2) Using genetically engineered VSIG10L knockout and VSIG10L S631G variant carrying mice to understand how VSIG10L contributes to the normal squamous epithelium  esophagitis  BE metaplasia  dysplasia  cancer progression; The significance of Project 1 is first to translate the clinical observation of racial disparity in BE and EAC into the laboratory to identify a causative genetic basis. Furthermore, the project will build on our successful discovery of the first familial susceptibility genetic variant by understanding how this gene functions in metaplastic transformation of Barrett's epithelium.