Investigating immune-microbiota interaction in lung cancer

研究肺癌中免疫-微生物群的相互作用

基本信息

批准号：
10406357
负责人：
Chengcheng Jin
金额：
$ 24.9万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10406357
关键词：
Address Adenocarcinoma Antibiotic Therapy Antibiotics Area Asthma Award Bacteria Bacterial Infections Binding Bioinformatics Biology Boston Cancer Etiology Cancer Patient Cessation of life Clinical Collaborations Communities Complex Cystic Fibrosis Development Disease Distal Engineering Gene Expression Profile Genes Genetic Genetically Engineered Mouse Germ-Free Goals Growth Human Human body Immune Immune response Immune system Immunology Immunophenotyping Individual Inflammation Institutes Interdisciplinary Study Intestines Laboratory Research Lesion Lower respiratory tract structure Lung Lung Adenocarcinoma Lung Neoplasms Lung diseases Lung infections Malignant Neoplasms Malignant neoplasm of lung Mediating Microbe Microbiology Modeling Molecular Mus Nebulizer Non-Small-Cell Lung Carcinoma Oral Outcome Pathogenesis Pathway interactions Pharmacology Phase Physiological Point Mutation Research Research Activity Research Personnel Resources Respiratory System Role Shapes Site Sterility T cell response TP53 gene Therapeutic Intervention Time Training Training Activity Tumor Burden Tumor Promotion aerosolized airway obstruction cancer therapy career career development commensal microbes experience experimental study frontier germ free condition gut microbiome gut microbiota human disease in vivo insight loss of function lung microbiota lung tumorigenesis microbial community microbiota mouse model neoplastic cell neutrophil new therapeutic target novel skills targeted treatment tool training opportunity treatment response tumor tumor growth tumor initiation tumor microenvironment tumor progression tumorigenesis γδ T cells

项目摘要

Project Summary/Abstract Commensal microbiota inhabits multiple human body sites, primarily in the intestine, and also along the respiratory tract including the lung. Intestinal microbiota has emerged as an important regulator of tumorigenesis and therapeutic response in several cancers, yet its role in lung cancer has not been clearly understood. Changes in the lung microbiota have been associated with several pulmonary disorders; bacterial infections are highly common in lung cancer patients and closely related to clinical outcomes, but the underlying biology has been elusive. Therefore, the proposed study aims to investigate the role of local (lung) and distal (intestinal) microbiota in lung cancer development by using a genetically-engineered mouse model that recapitulates the activating point mutation of Kras and loss of p53 in human lung adenocarcinoma. Our preliminary results showed that tumor growth was associated with increased bacterial burden and altered microbiota composition in the lung, while systemic depletion of microbiota significantly reduced inflammation and tumor burden, suggesting that the development of a disordered microbiota may induce a dysregulated immune response to promote lung cancer progression. Here we propose to further interrogate the complex interactions among commensal microbiota, the host immune system and developing tumor cells to elucidate the cellular and molecular mechanism(s) by which microbiota promotes tumor initiation and progression. Specifically, we will (1) establish the role of microbiota-induced γδ T cells in lung tumorigenesis, (2) determine the effector mechanism(s) of γδ T cells in mediating microbiota-driven tumor promotion, (3) identify the tumor- promoting bacteria in the lung or intestinal microbiota. While the current research aims to reveal the role of commensal microbiota in lung cancer by shaping the tumor associated immune response, continued efforts in the independent phase of this award will be focused on identifying the bacterial species and responding host pathways involved in tumor promotion which may be targeted for therapeutic intervention in lung cancer. My career goal is to independently direct an academic research laboratory addressing questions pertaining to the biology and mechanism of immune-microbiota interaction in cancer. While I have extensive experience in studying immunology and microbiota, and the use of genetic mouse models, the K99 phase of this project will allow me to receive further training in advanced bioinformatics and microbiology skills, and to develop novel gene-editing tools in vivo using autochthonous mouse models of lung cancer. Moreover, I will take advantage of the superb training opportunities and resources available at the MIT/Broad Institute and further establish collaborations and networks with the strong, multidisciplinary research communities in the Boston area. These proposed training and research activities will greatly promote my career development towards an independent investigator in the frontier of research on immune-microbiota interaction, a rising field that can significantly extend our understanding of cancer and provide us guidance towards more effective cancer therapies.

项目概要/摘要共生微生物群栖息在人体的多个部位，主要是在肠道中，也沿着肠道包括肺在内的呼吸道微生物群已成为重要的调节因子。多种癌症的肿瘤发生和治疗反应，但其在肺癌中的作用尚未明确据了解，肺部微生物群的变化与多种肺部疾病有关。感染在肺癌患者中非常常见，并且与临床结果密切相关，但因此，拟议的研究旨在调查局部（肺）的作用。使用基因工程小鼠模型研究肺癌发展中的远端（肠道）微生物群概括了人类肺腺癌中 Kras 的激活点突变和 p53 的缺失。初步结果表明肿瘤生长与细菌负荷增加有关肺部微生物群组成，而全身微生物群的消耗显着减少炎症和肿瘤负荷，表明紊乱的微生物群的发展可能会导致失调在这里，我们建议进一步研究这一复合体。共生微生物群、宿主免疫系统和发育中的肿瘤细胞之间的相互作用以阐明微生物群促进肿瘤发生和进展的细胞和分子机制。具体来说，我们将 (1) 确定微生物群诱导的 γδ T 细胞在肺肿瘤发生中的作用，(2) 确定 γδ T 细胞介导微生物群驱动的肿瘤促进的效应机制，(3) 确定肿瘤- 促进肺部或肠道微生物群中的细菌，而当前的研究旨在揭示其作用。通过塑造肿瘤相关的免疫反应来研究肺癌中的共生微生物群，继续努力该奖项的独立阶段将重点关注确定细菌种类和响应宿主参与肿瘤促进的途径可能是肺癌治疗干预的目标。我的职业目标是独立指导学术研究实验室解决以下问题癌症免疫-微生物群相互作用的生物学和机制，而我在这方面拥有丰富的经验。研究免疫学和微生物群，以及遗传小鼠模型的使用，该项目的 K99 阶段将让我接受高级生物信息学和微生物学技能的进一步培训，并开发新的此外，我将利用使用本地肺癌小鼠模型的体内基因编辑工具。麻省理工学院/博德研究所提供的一流培训机会和资源，并进一步建立与波士顿地区强大的多学科研究社区的合作和网络。拟议的培训和研究活动将极大地促进我的职业发展，走向独立免疫-微生物群相互作用研究前沿的研究员，这是一个新兴领域，可以显着扩展我们对癌症的理解，并为我们提供更有效的癌症治疗的指导。