Deciphering the Molecular Genetics of VSIG10L in Barrett's Neoplasia

破译巴雷特瘤形成中 VSIG10L 的分子遗传学

• 批准号: 10713939
• 负责人: AMITABH CHAK
• 金额: $ 54.97万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 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/10713939
• 关键词: 3-Dimensional; Ablation; Acceleration; Address; Affect; Age Months; Barrett Esophagus; Barrett' s carcinogenesis; Barrett' s neoplasia; Biological Assay; Biological Markers; Biopsy; Cell-Cell Adhesion; Cells; Chemopreventive Agent; Complement 3d; Complex; Desmosomes; Development; Disease; Distal; Duct (organ) structure; Dysplasia; Electron Microscopy; Ephrin-B2; Epithelium; Esophageal Adenocarcinoma; Esophageal injury; Esophageal mucous membrane; Esophagus; Etiology; Exhibits; Exposure to; Family; Functional disorder; Genes; Genetic; Genotype; Germ-Line Mutation; Gland; Goals; Homeostasis; Human; Impairment; Inflammation; Inherited; Injury; Intercellular Junctions; Interleukin-1 beta; Knock-in; Knock-in Mouse; Knock-out; Knockout Mice; Lead; Lesion; Malignant - descriptor; Malignant Neoplasms; Metaplasia; Methods; Modeling; Molecular; Molecular Genetics; Morphology; Mucous Membrane; Mus; Mutant Strains Mice; Mutation; Organoids; Orthologous Gene; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Phosphotransferases; Pilot Projects; Predisposition; Recurrence; Reflux; Risk; Role; Signal Transduction; Squamous Cell; Squamous Differentiation; Squamous Epithelium; Submucosa; Testing; Therapeutic; Tissues; United States; Variant; cancer prevention; carcinogenesis; clinical implementation; comparison control; deoxycholate; design; evidence base; exome sequencing; experimental study; follow-up; genotoxicity; healing; human subject; indexing; induced pluripotent stem cell; injury and repair; interstitial; microscopic imaging; mouse model; mutant; novel; prevent; programs; prospective; segregation; synergism; transcriptomic profiling; transdifferentiation; translational goal; wound healing

PROJECT SUMMARY/ABSTRACT The etiology of Barrett's esophagus (BE), a molecularly complex disorder of the distal esophagus, remains elusive. Patients with BE are at an increased risk of developing esophageal adenocarcinoma (EAC), a lethal, increasingly prevalent, and the most common esophageal malignancy in the U.S. Our long-term objective is to identify the causative mechanisms underlying the onset and malignant progression of BE, and to develop evidence-based biomarkers and chemopreventive/therapeutic strategies for subsequent clinical implementation. Project 1 of this program is based on our prior discovery of a novel germline susceptibility mutation in VSIG10L (S631G) that modulates the epithelial integrity of squamous epithelium. VSIG10L is expressed in suprabasal cells as squamous epithelium matures. Furthermore, we have generated mice that are either null for Vsig10l or carry the mouse ortholog of the human S631G variant. Homozygous Vsig10l knockout (KO) and homozygous S631G knockin (KI) mice are both viable. Electron microscopy imaging demonstrates decreased desmosomal cell to cell junctions in the suprabasal squamous cells of mice with altered VSIG10L. Further, both mouse genotypes initially develop multilayered epithelium at 12 months of age and BE like metaplasia by 24 months at the squamo-columnar junction (SCj) upon exposure to genotoxic/oxidative stress (Deoxycholate). The three Aims of Project 1 strategically address how mutations in VSIG10L lead to a susceptibility to BE. Aim 1 will define phenotypic and molecular alterations affected by VSIG10L mutations in three dimensional organotypic cultures. Aim 2 will define phenotype of our mouse models and identify molecular alterations that lead to BE like metaplasia and dysplasia. Aim 3 studies how VSIG10L expression is associated with a susceptibility to develop BE in human subjects. Collectively, our proposed studies will delineate the role of VSIG10L in esophageal homeostasis, uncovering novel mechanisms of BE-EAC pathogenesis.

项目摘要/摘要 Barrett食管（BE）的病因是一种远端食管的分子复杂疾病 难以捉摸。患有BE的患者患食道腺癌（EAC）的风险增加，致命， 越来越普遍，并且是美国最常见的食管恶性肿瘤，我们的长期目标是 确定BE发作和恶性进展的原因，并发展 基于证据的生物标志物和化学预防/治疗策略，用于随后的临床实施。 该程序的项目1基于我们先前发现了VSIG10L中新型种系敏感性突变 （S631G）调节鳞状上皮的上皮完整性。 VSIG10L在suprabasal中表达 细胞为鳞状上皮成熟。此外，我们生成的小鼠要么是vsig10l或 携带人类S631G变体的小鼠直系同源物。纯合VSIG10L淘汰（KO）和纯合子 S631g敲击蛋白（Ki）小鼠都是可行的。电子显微镜成像表明脱骨体降低 vSig10l改变的小鼠上鳞状细胞中细胞连接的细胞连接。此外，两种鼠标 基因型最初在12个月大的时候开发多层上皮，并且在24个月的时间像化生 暴露于遗传毒性/氧化应激（脱氧胆酸盐）后，鳞状柱交界处（SCJ）。三个 项目1的目的从战略上解决了VSIG10L中的突变如何导致易感性。 AIM 1将定义 在三维器官培养物中受VSIG10L突变影响的表型和分子改变。 AIM 2将定义我们的小鼠模型的表型，并确定导致类似的分子改变 变质和发育不良。 AIM 3研究VSIG10L表达与发展的易感性有关 成为人类主题。总的来说，我们提出的研究将描述VSIG10L在食管中的作用 体内平衡，发现BE-EAC发病机理的新型机制。