Early TP53 Mutations and Genomic Doubling as a Novel Path for Barrett's Esophagus Progression

早期 TP53 突变和基因组加倍是巴雷特食管进展的新途径

• 批准号: 10380456
• 负责人: Matthew D Stachler
• 金额: $ 8.16万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380456
• 关键词: Acids; American; Anatomy; Aneuploidy; Applications Grants; Area; Barrett Epithelium; Barrett Esophagus; Bile Reflux; Bile fluid; Biological Markers; Biological Models; Biology; Board Certification; California; Camellia sinensis; Cancer Biology; Chronic; DNA Sequence Alteration; Discipline; Doctor of Medicine; Doctor of Philosophy; Dysplasia; Early Diagnosis; Esophageal Adenocarcinoma; Esophageal Intraepithelial Neoplasia; Esophageal Tissue; Esophagus; Exposure to; Funding; Gastroesophageal reflux disease; Gastrointestinal Diseases; Genetic; Genomics; Goals; Histologic; In Vitro; Incidence; Intestines; K-Series Research Career Programs; Malignant Neoplasms; Malignant neoplasm of esophagus; Massive Parallel Sequencing; Mentors; Mentorship; Modeling; Molecular; Molecular Genetics; Mutation; Neoplastic Cell Transformation; Oncogenes; Pathology; Pathway interactions; Physicians; Process; Research; Research Personnel; Risk; Role; San Francisco; Scientist; TP53 gene; Testing; Training; United States National Institutes of Health; Universities; bile salts; career; career development; clinically significant; disorder risk; gastrointestinal; high risk; in vivo; in vivo Model; laser capture microdissection; model development; mouse model; novel; research study; response; screening

PROJECT SUMMARY Intestinalization of the esophagus, termed Barrett’s esophagus (BE), is thought to develop in response to chronic acid and bile reflux and carries great clinical significance because it is the precursor to esophageal adenocarcinoma (EAC). The incidence of BE is quite high, estimated to be found in at least 1:100 people. While relatively few with BE progress to cancer there is great importance to being able to detect those at risk of progression. Efforts to screen for high risk disease in those with BE have, to date, not been very successful. Therefore, there is profound need to define the process by which BE progresses into EAC, to develop biomarkers to diagnose early progression and assess progression risk in BE tissues. The objective of this mentored research career development proposal is to investigate the molecular underpinnings of Barrett’s esophagus progression with the long term goal to develop better screening strategies and biomarkers to identify those at risk of progression at an early curable stage. To determine when and where key alterations in BE progression occur, laser capture microdissection and sequencing of histologically defined areas of BE, dysplasia, and EAC will be performed. These alterations will then be modeled in both an in vitro and in vivo setting to determine their functional significance. The role of acid and bile exposure to BE progression and how these exposures interact with genetic alterations will be investigated using the same model systems. These research studies encompass a wide array of disciplines including gastrointestinal pathology, Barrett’s biology, massively parallel sequencing/genetics, and in vitro and in vivo (mouse) model development, which together will help define the process of BE progression as well as provide a well rounded career development pathway to becoming an independent investigator through the following specific aims: Aim 1: To define the timing of TP53 mutations and genomic doubling in Barrett’s esophagus progression relative to onset of dysplasia and acquisition of other genomic alterations. Aim 2: To test the hypothesis in in vitro and in vivo models of Barrett’s esophagus that TP53 mutations facilitate acquisition of genomic doubling, aneuploidy, and oncogene amplification leading to neoplastic transformation. Aim 3: To determine the effect of acidic pH and bile salt exposure on Barrett's epithelial progression. This career development award candidate is a M.D./Ph.D. with board certification in anatomic and molecular genetic pathology. The research proposed in this grant application will be conducted under the co- mentorship of Dr. Thea Tlsty at the University of California San Francisco. The candidate is committed to a career as a physician scientist and seeks further training to facilitate his transition to become a NIH-funded independent investigator in the field of gastrointestinal disease.

项目摘要 食管的肠化，称为巴雷特食管（BE），被认为是在响应 慢性酸和胆汁反流，具有重要的临床意义，因为它是食管癌的前兆， 腺癌（EAC）。BE的发病率相当高，估计至少在1：100的人群中发现。而 相对较少的BE进展为癌症，能够检测出那些处于癌症风险中的人是非常重要的。 进展迄今为止，在BE患者中筛查高危疾病的努力并不十分成功。 因此，非常需要确定BE进展为EAC的过程，以开发生物标志物 诊断BE组织中的早期进展并评估进展风险。这项研究的目的是 我的职业发展计划是研究巴雷特食管进展的分子基础 长期目标是开发更好的筛查策略和生物标志物，以识别那些有 在可治愈的早期阶段进展。为了确定BE进展中的关键改变发生的时间和地点， 激光捕获显微切割和BE、异型增生和EAC的组织学定义区域的测序将是 执行。然后将在体外和体内环境中对这些改变进行建模，以确定它们的 功能意义。酸和胆汁暴露对BE进展的作用以及这些暴露如何相互作用 将使用相同的模型系统研究遗传改变。这些研究包括 包括胃肠道病理学，巴雷特生物学，大规模并行 测序/遗传学，以及体外和体内（小鼠）模型开发，这些都将有助于定义 的BE进展过程，以及提供一个全面的职业发展途径，成为一个 独立调查员，具体目标如下： 目的1：确定TP 53突变和基因组加倍在Barrett食管进展中的时间 相对于发育异常的发生和其他基因组改变的获得。 目的2：在Barrett食管的体外和体内模型中验证TP 53突变的假设， 促进获得基因组加倍、非整倍体和致癌基因扩增，导致肿瘤 转型 目的3：确定酸性pH和胆盐暴露对Barrett上皮进展的影响。 职业发展奖候选人是一名医学博士/博士拥有解剖学和 分子遗传病理学这项资助申请所建议的研究将在联合基金下进行， 在加州旧金山弗朗西斯科的Thea Tlsty博士的指导下。候选人致力于 职业生涯作为一个医生科学家，并寻求进一步的培训，以促进他的过渡，成为一个NIH资助的 胃肠道疾病领域的独立研究者。