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‘s食道(BE)是一种位于食道远端的复杂的分子疾病，其病因学仍未得到证实。 难以捉摸。患有BE的患者患食管腺癌(EAC)的风险增加，EAC是一种致命的 在美国日益流行，也是最常见的食道恶性肿瘤。我们的长期目标是 明确BE发病和恶性进展的致病机制，并发展 循证生物标记物和后续临床实施的化学预防/治疗策略。 该计划的项目1是基于我们先前在VSIG10L中发现的一种新的生殖系易感性突变 (S631G)，调节鳞状上皮的上皮完整性。VSIG10L以超碱基形式表达 细胞随着鳞状上皮的成熟而成熟。此外，我们已经生成了Vsig10l为空或 携带人类S631G变异的小鼠直系同源基因。纯合子Vsig10l基因敲除(KO)和纯合子 S631G敲门(KI)小鼠均存活。电子显微镜成像显示桥粒减少 VSIG10L基因突变小鼠基底上鳞状细胞的细胞间连接。此外，这两个鼠标 基因型最初在12个月龄时形成多层上皮，在24个月龄时类似化生 暴露在基因毒性/氧化应激(脱氧胆酸盐)下的鳞状-柱状连接(SCJ)。三位一体 项目1的目标是战略性地解决VSIG10L突变是如何导致易感性的问题。目标1将定义 三维器官培养中VSIG10L突变对表型和分子改变的影响。 目标2将定义我们的小鼠模型的表型，并确定导致类似于 化生和异型增生。AIM 3研究VSIG10L表达如何与发病易感性相关 成为人类的研究对象。总之，我们建议的研究将描绘VSIG10L在食道中的作用 动态平衡，揭示BE-EAC发病的新机制。