Integration of early genetic alterations and inflammation in gastroesophageal premalignancy

胃食管癌前病变中早期基因改变和炎症的整合

• 批准号: 10335249
• 负责人: Nilay Sethi
• 金额: $ 15.8万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10335249
• 关键词: Advisory Committees; Basic Science; Bass; Cancer Biology; Career Choice; Cell Culture System; Cell physiology; Cells; Chronic; Clinical; Complement; Coupled; DNA Sequence Alteration; Dana-Farber Cancer Institute; Data; Development; Disease; Environment; Esophagogastric Junction; Evolution; Experimental Designs; Experimental Models; Exposure to; Feedback; Fluorescent Probes; Gastroesophageal reflux disease; Gastrointestinal Diseases; Gastrointestinal tract structure; Genetic; Genetically Engineered Mouse; Genomics; Goals; Growth; Human; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-1 beta; LGR5 gene; Label; Laboratories; Laboratory Research; Lesion; Malignant Neoplasms; Mediating; Mediator of activation protein; Medical Oncologist; Mentors; Mentorship; Methods; Modeling; Molecular; Molecular Biology; Molecular and Cellular Biology; Mutate; Mutation; Organoids; Pathway interactions; Patients; Positioning Attribute; Precancerous Conditions; Prevention strategy; Production; Program Development; Research; Research Personnel; Research Proposals; Risk Factors; Sampling; System; TP53 gene; Testing; Therapeutic; Training; Translational Research; Work; base; cancer genomics; cancer prevention; career development; clinical risk; cytokine; design; exome sequencing; experimental study; gastroesophageal cancer; in vivo; in vivo Model; innovation; insight; mRNA sequencing; mouse model; mutant; novel; premalignant; research and development; screening; stem cells; tenure track; tumor-immune system interactions

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.

项目概要 胃肠道的慢性炎症促进癌前病变的发展 具有潜在的破坏性后果。定义与之合作的精确分子介体 支持癌前病变的炎症将为有效预防策略的设计提供信息。基因组 对癌前胃食管 (GE) 病变的注释显示，TP53 突变频繁发生，并且 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 细胞提供产生癌前疾病的选择性优势。这 这项指导性研究职业发展提案的目标是将我们最近在癌症方面的发现结合起来 基因组学与新型小鼠炎症模型以获得对癌前病变的新概念见解 状态。为此，我们设计了一个实验系统，将 GE 细胞中的 TP53 改变与 使用新型小鼠模型研究两种炎症模式（目标 1）。通过标记 TP53 突变 GE 细胞 荧光探针，我们将能够追踪炎症背景下癌前疾病的演变。 此外，对这些研究中的癌前病变进行直接分析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 系统地测试与疾病相关的炎症相关因素对细胞的影响 TP53 改变 GE 细胞的功能（目标 2）。我们的初步数据表明，TP53 的缺失在癌前病变中发挥着重要作用。 GE 细胞刺激炎症细胞因子的产生，这意味着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 TP53 改变在 GE 癌前病变中诱导炎症途径的重要性（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。 我是一名肿瘤内科医生，具有细胞和分子生物学研究背景。我的长期目标 目标是成为一名具有胃肠道疾病专业知识的终身教授独立实验室研究者。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 癌前胃肠道疾病的研究，重点是炎症、基因组学和治疗。 在我提议的培训期间，我将在 Adam Bass 博士的实验室进行指导性研究 达纳法伯癌症研究所。我很幸运有一个出色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。加上优秀的制度环境、培养计划、职业生涯 发展计划中，所提出的研究将使我能够实现我的长期职业愿望。