Integration of early genetic alterations and inflammation in gastroesophageal premalignancy

项目摘要 胃肠道的慢性炎症可促进癌前病变的发展， 潜在的毁灭性后果定义与之合作的精确分子介质 炎症支持癌前病变将为设计有效的预防策略提供信息。基因组 癌前胃食管（GE）病变的注释显示TP 53突变频繁发生， 预测癌症的发展基于这些观察，我们假设慢性炎症 为携带TP 53突变的GE细胞产生癌前病变提供了选择性优势。的 这个指导研究职业发展建议的目标是将我们最近在癌症方面的发现联合收割机 基因组学与新的小鼠炎症模型，以获得新的概念见解癌前病变 状态为此，我们设计了一个实验系统，将GE细胞中的TP 53改变与 两种模式的炎症使用一种新的小鼠模型（目的1）。通过用荧光素标记TP 53突变体GE细胞， 荧光探针，我们将能够跟踪炎症背景下癌前病变的演变。 此外，直接分析这些研究的癌前病变将有助于阐明特定的突变 和/或能够使TP 53突变GE细胞具有选择优势的途径。我们还将利用体外 系统地测试疾病相关炎症相关因子对细胞增殖的影响， TP 53改变GE细胞的功能（目的2）。我们的初步数据表明，在癌前病变中TP 53的缺失， GE细胞刺激炎症细胞因子的产生，暗示潜在的恶性反馈循环。 使用小鼠模型、类器官培养物和患者样本的补充，我们将研究功能性 在癌前GE病变中由TP 53改变诱导的炎症途径的意义（目的3）。 总的来说，这些研究为GE癌前病变的癌症预防带来了巨大的希望。 我是一名具有细胞和分子生物学研究背景的医学肿瘤学家。我的长期目标 是成为一个终身制的独立实验室研究员，在胃肠道疾病方面有专长。我 我致力于领导一个定义关键功能机制的基础和转化研究实验室 胃肠道癌前病变的研究，重点是炎症、基因组学和治疗学。 在我计划的培训期间，我将在亚当·巴斯博士的实验室进行指导研究。 丹娜-法伯癌症研究所。我很幸运有一个特殊的咨询委员会来帮助指导我的工作。 研究和职业发展，包括William Kaelin博士，Benjamin Ebert博士，Timothy Wang博士，Anil博士 Rustgi和Kevin Haigis博士。再加上出色的机构环境、培训计划和职业生涯 发展计划，建议的研究将使我能够实现我的长期职业抱负。

PROJECT SUMMARY Chronic inflammation in the gastrointestinal tract promotes the development of premalignant lesions imbued with potential devastating consequences. Defining the precise molecular mediators that collaborate with inflammation to endorse premalignancy will inform the design of effective prevention strategies. Genomic annotation of premalignant gastroesophageal (GE) lesions revealed that TP53 mutations occur frequently and predict the progression to cancer. Based on these observations, we hypothesize that chronic inflammation provides a selective advantage for GE cells harboring TP53 mutations to generate premalignant disease. The objective of this mentored research career development proposal is to combine our recent findings in cancer genomics with novel mouse models of inflammation to derive new conceptual insights into the premalignant state. To this end, we have designed an experimental system that integrates TP53 alterations in GE cells with two modes of inflammation using a novel mouse model (Aim 1). By labeling TP53 mutant GE cells with fluorescent probes, we will be able to track the evolution of premalignant disease in the setting of inflammation. Furthermore, direct analysis of premalignant lesions from these studies will help elucidate specific mutations and/or pathways that enable a selective advantage for TP53 mutant GE cells. We will also utilize an in vitro system to systematically test the impact of disease-relevant inflammation-associated factors on cellular functions of TP53 altered GE cells (Aim 2). Our preliminary data showed that deletion of TP53 in premalignant GE cells stimulates the production of inflammatory cytokines, implicating a potential vicious feedback cycle. Using a complement of mouse models, organoid culture, and patient samples, we will investigate the functional significance of inflammation pathways induced by TP53 alterations in premalignant GE lesions (Aim 3). Overall, these studies hold tremendous promise for cancer prevention in GE premalignancy. I am a medical oncologist with a research background in cellular and molecular biology. My long-term goal is to become a tenure-track independent laboratory investigator with expertise in gastrointestinal diseases. I am dedicated to leading a basic and translational research laboratory that defines key functional mechanisms of premalignant gastrointestinal disease with an emphasis on inflammation, genomics, and therapeutics. During my proposed training period, I will perform mentored research in the laboratory of Dr. Adam Bass at the Dana-Farber Cancer Institute. I am fortunate to have an exceptional advisory committee to help guide my research and career development including Dr. William Kaelin, Dr. Benjamin Ebert, Dr. Timothy Wang, Dr. Anil Rustgi, and Dr. Kevin Haigis. Coupled with an outstanding institutional environment, training plan, and career development program, the proposed research will enable me to achieve my long-term career aspirations.