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.

项目总结/摘要 Barrett食管（BE）是一种远端食管的分子复杂疾病，其病因仍然是 难以捉摸。BE患者发生食管腺癌（EAC）的风险增加， 越来越普遍，是美国最常见的食管恶性肿瘤。我们的长期目标是 确定BE发病和恶性进展的致病机制，并制定 循证生物标志物和化学预防/治疗策略，用于后续临床实施。 该项目的项目1是基于我们先前在VSIG 10 L中发现的一种新的生殖系易感性突变 （S631 G），其调节鳞状上皮的上皮完整性。VSIG 10 L在基底膜上表达， 鳞状上皮细胞成熟。此外，我们已经产生了Vsig 10 l无效或 携带人S631 G变体的小鼠直系同源物。纯合Vsig 101敲除（KO）和纯合 S631 G敲入（KI）小鼠均存活。电镜成像显示桥粒减少 VSIG 10 L改变的小鼠基底上鳞状细胞中的细胞间连接。此外，两种小鼠 基因型最初在12个月大时形成多层上皮，24个月大时形成BE样化生， 在暴露于遗传毒性/氧化应激（脱氧胆酸盐）时的鳞状-柱状连接（SCj）。三 项目1的目的是战略性地解决VSIG 10 L突变如何导致BE易感性。目标1将定义 在三维器官型培养物中受VSIG 10 L突变影响的表型和分子改变。 目的2将确定我们的小鼠模型的表型，并鉴定导致BE样的分子改变。 化生和发育不良。目的3研究VSIG 10 L表达如何与发展中国家的易感性相关。 在人类受试者中。总的来说，我们提出的研究将描述VSIG 10 L在食管癌中的作用。 稳态，揭示BE-EAC发病机制的新机制。