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

基本信息

批准号：
9929248
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
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-15 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9929248
关键词：
3-Dimensional Acids Address American Anatomy Aneuploidy Applications Grants Archives Area Asses 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 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 Tissues 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

项目摘要

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（由应用提供）：被认为是对慢性酸和胆汁反射X的肠道化，称为Barrett的食管（BE），并且具有极大的临床意义，因为它是食管食管腺癌（EAC）的先驱。 BE的事件很高，估计至少有1：100人。虽然相对较少的癌症进展，但能够检测到有进展风险的人非常重要。迄今为止有筛查高风险疾病的努力，而不是他们非常成功。非常需要定义进入EAC的过程，以开发生物标志物来诊断组织中的早期进展和评估进展风险。这项修改研究职业发展计划的目的是研究巴雷特食管进展的分子基础，长期目标是制定更好的筛查策略和生物标志物，以确定在早期可愈合阶段有进展风险的人。为了确定BE进展的何时何地发生，将执行激光捕获微分辨率和BE，发育不良和EAC的组织学区域的微分解和测序。然后，这些改变将在体外和体内设置中建模，以确定它们的功能意义。将使用相同的模型系统研究酸和胆汁暴露于进展的作用以及这些暴露与遗传变化的相互作用。 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 become an independent investigator through the following specific aims: Aim 1: To define the timing of TP53 mutations and genomic dubing in巴雷特的食管发展相对于发育不良的发作和其他基因组改变的获取。目的2：测试Barrett食管的体外和体内模型中TP53突变的假设有助于获得基因组倍增，非整倍和癌基因扩增，从而导致肿瘤转化。目标3：确定酸性pH和胆汁盐暴露对Barrett上皮进展的影响。该职业发展奖候选人是M.D./ph.d。具有解剖和分子遗传病理学的董事会认证。本赠款申请中提出的研究将根据DR的委托书进行。 Dana-Farber癌症研究所的Massimo Loda和Adam Bass以及波士顿的Brigham及其妇女医院。候选人致力于从事物理科学家的职业，并寻求进一步的培训，以促进他的过渡，成为胃肠道疾病领域的NIH资助的独立研究者。