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

项目总结 被称为巴雷特食道(BE)的食管肠化被认为是作为反应而发展起来的 对慢性胃酸和胆汁反流具有重要的临床意义，因为它是食道的前驱 腺癌(EAC)。BE的发病率相当高，估计至少在1：100人中发现。而当 随着癌症的进展，相对较少的人能够检测到那些有风险的人 进步。到目前为止，在BE患者中筛查高危疾病的努力并不是非常成功。 因此，有必要明确BE进展为EAC的过程，开发生物标记物 目的：诊断BE组织的早期进展并评估进展风险。这项有指导的研究的目标是 职业发展计划是研究巴雷特食道进展的分子基础 长期目标是开发更好的筛查策略和生物标记物来识别那些有风险的人 进展处于可治愈的早期阶段。为了确定BE进程中的关键改变何时何地发生， 将对BE、异型增生和EAC的组织学定义区域进行激光捕获显微解剖和测序 已执行。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。酸和胆汁暴露在疾病进展中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来研究基因改变。这些研究包括 广泛的学科，包括胃肠病理学，巴雷特的生物学，大量平行 测序/遗传学，以及体外和体内(小鼠)模型的开发，这将有助于定义 BE的发展过程，以及提供全面的职业发展途径，成为 独立调查员通过以下具体目标： 目的1：确定Barrett‘s食道进展中TP53突变和基因组加倍的时间 相对于异常增殖症的开始和其他基因组改变的获得。 目的2：在体外和体内Barrett‘s食道模型中验证TP53突变的假说 促进基因组加倍、非整倍体和癌基因扩增导致肿瘤的获得 转型。 目的：探讨酸性pH和胆盐暴露对Barrett‘s上皮病变的影响。 这位职业发展奖候选人是医学博士/博士学位，拥有解剖学和 分子遗传病理学。在这项拨款申请中建议的研究将在联合- 加州大学旧金山分校西娅·蒂尔斯蒂博士的导师。候选人将致力于 作为一名内科科学家的职业生涯，并寻求进一步的培训，以促进他过渡到NIH资助的 胃肠道疾病领域的独立研究员。

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.