Integration of early genetic alterations and inflammation in gastroesophageal premalignancy

项目总结 胃肠道慢性炎症促进癌前病变的发展 具有潜在的毁灭性后果。定义与之协作的精确分子介体 为癌前病变代言的炎症将为设计有效的预防策略提供信息。基因组学 对胃食道癌前病变的注释显示，TP53突变频繁发生， 预测癌症的进展。基于这些观察，我们假设慢性炎症 为携带TP53突变的GE细胞产生癌前疾病提供了选择性优势。这个 这项有指导的研究职业发展建议的目标是结合我们在癌症方面的最新发现 用新的小鼠炎症模型进行基因组学研究，以获得对癌前病变的新的概念性见解 州政府。为此，我们设计了一个实验系统，将GE细胞中的TP53改变与 使用一种新的小鼠模型的两种炎症模式(目标1)。通过标记TP53突变型GE细胞 有了荧光探针，我们将能够在炎症的背景下跟踪癌前疾病的演变。 此外，从这些研究中直接分析癌前病变将有助于阐明特定的突变。 和/或使TP53突变GE细胞具有选择性优势的途径。我们还将利用体外培养的 系统测试疾病相关炎症相关因子对细胞的影响 TP53改变GE细胞的功能(目标2)。我们的初步数据显示，在癌前病变中，TP53基因缺失 GE细胞刺激炎性细胞因子的产生，暗示着一个潜在的恶性循环。 使用补充的小鼠模型，器官培养，和患者样本，我们将研究功能 癌前病变中TP53改变诱导的炎症途径的意义(目标3)。 总体而言，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内科肿瘤学家。我的长期目标 是成为一名拥有胃肠道疾病专业知识的终身教职独立实验室研究员。我 我致力于领导一个基础和翻译研究实验室，定义关键的功能机制 以炎症、基因组学和治疗学为重点的癌前胃肠道疾病。 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 达纳-法伯癌症研究所。我很幸运有一个杰出的咨询委员会来帮助指导我的 研究和职业发展，包括威廉·凯林博士、本杰明·埃伯特博士、蒂莫西·王博士、阿尼尔博士 Rustgi和Kevin Haigis博士。再加上优秀的制度环境、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长期的职业抱负。

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.