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: 9666941
• 负责人: Matthew D Stachler
• 金额: $ 17.21万
• 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/9666941
• 关键词: 3-Dimensional; Acids; Address; American; Anatomy; Aneuploidy; Applications Grants; Archives; Area; Asses; Barrett Epithelium; Barrett Esophagus; Bass; Bile Reflux; Bile fluid; Biological; Biological Markers; Biological Models; Biology; Board Certification; Boston; CDKN2A gene; Cancer Biology; Cells; Chronic; Clonal Expansion; Collection; DNA Sequence Alteration; Dana-Farber Cancer Institute; Data; Development; Diagnosis; Diagnostic; Discipline; Disease; Doctor of Medicine; Doctor of Philosophy; Dysplasia; Early Diagnosis; Environmental Risk Factor; Epithelial; Epithelium; Esophageal Adenocarcinoma; Esophageal Intraepithelial Neoplasia; Esophageal Tissue; Esophagus; Event; Experimental Models; Exposure to; Foundations; Functional disorder; Funding; Gastroesophageal reflux disease; Gastrointestinal Diseases; Genetic; Genetically Engineered Mouse; Genome; Genomic Instability; Genomics; Goals; Histologic; Hospitals; Human; In Vitro; Incidence; Intestines; K-Series Research Career Programs; Malignant Neoplasms; Malignant neoplasm of esophagus; Massive Parallel Sequencing; Mediator of activation protein; Mentors; Mentorship; Minority; Modeling; Molecular; Molecular Genetics; Mutation; Neoplastic Cell Transformation; Oncogenes; Oncogenic; Pathologic; Pathology; Pathway interactions; Patients; Phase; Physicians; Process; Research; Research Personnel; Risk; Role; Sampling; Scientist; System; TP53 gene; Testing; Training; Tumor Suppressor Proteins; United States National Institutes of Health; Woman; bile salts; career; career development; clinical application; clinically significant; disorder risk; gastrointestinal; high risk; in vivo; in vivo Model; insight; laser capture microdissection; model development; mouse model; mutant; novel; novel strategies; prevent; public health relevance; research study; response; screening; spatial relationship; tumor progression

 DESCRIPTION (provided by applicant): 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 Drs. Massimo Loda and Adam Bass at Dana-Farber Cancer Institute and Brigham and Women's Hospital in Boston. 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.

 描述（由申请方提供）：食管肠化，称为巴雷特食管（BE），被认为是对慢性酸和胆汁反流的反应，具有重要的临床意义，因为它是食管腺癌（EAC）的前兆。BE的发病率相当高，估计至少在1：100的人群中发现。虽然相对较少的BE进展为癌症，但能够检测那些有进展风险的人非常重要。到目前为止，在BE患者中筛查高危疾病的努力还没有取得成功。 非常成功。因此，非常需要定义BE进展为EAC的过程，开发生物标志物以诊断早期进展并评估BE组织中的进展风险。这个指导研究职业发展建议的目的是调查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，以识别那些在早期可治愈阶段有进展风险的人。为了确定BE进展的关键变化发生的时间和位置，将对组织学定义的BE、异型增生和EAC区域进行激光捕获显微切割和测序。然后将在体外和体内环境中对这些改变进行建模，以确定其功能意义。将使用相同的模型系统研究酸和胆汁暴露对BE进展的作用以及这些暴露如何与遗传改变相互作用。这些研究涵盖了广泛的学科，包括胃肠道病理学，巴雷特生物学，大规模平行测序/遗传学，体外和体内（小鼠）模型开发，这些研究将有助于定义BE进展的过程，并提供一个全面的职业发展途径，通过以下具体目标成为独立的研究者：目标1：确定Barrett食管进展中TP 53突变和基因组加倍相对于异型增生发作和获得其他基因组改变的时间。目标二：在Barrett食管的体外和体内模型中检验TP 53突变促进获得基因组加倍、非整倍体和癌基因扩增导致肿瘤转化的假设。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委员会认证本资助申请中提出的研究将在Dana-Farber癌症研究所和波士顿布里格姆妇女医院的Massimo Loda博士和Adam Bass博士的共同指导下进行。候选人致力于作为一名医生科学家的职业生涯，并寻求进一步的培训，以促进他的过渡，成为一名NIH资助的胃肠道疾病领域的独立研究者。