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Elucidating the role of the Nrf2 anti-oxidant pathway in lung adenocarcinoma

阐明 Nrf2 抗氧化途径在肺腺癌中的作用

基本信息

批准号：
9013263
负责人：
Thales Papagiannakopoulos
金额：
$ 19.01万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9013263
关键词：
Accounting Adenocarcinoma Cell Alleles Animal Model Antioxidants Area Attenuated Award Biochemical Bypass CRISPR/Cas technology Cancer Biology Cancer Etiology Career Transition Award Catabolism Cell Line Cell Survival Cells Cessation of life Clinical Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Communities Cre-LoxP Dedications Development Educational workshop Engineering Environment Enzymes Fostering Foundations Frequencies Genes Genetic Genetic Epistasis Genetically Engineered Mouse Glucose Goals Growth Health Histologic Homeostasis Human Human Cell Line In Vitro Institutes Intention Investments Isotope Labeling Label Laboratories Lead Lung Adenocarcinoma Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediating Metabolic Metabolic Pathway Metabolism Methods Molecular Mus Mutagens Mutate Mutation Non-Small-Cell Lung Carcinoma Nutrient Outcome Output Oxidative Stress Oxidative Stress Pathway Pathway interactions Phase Play Postdoctoral Fellow Reactive Oxygen Species Recruitment Activity Regulation Research Research Project Grants Role Shapes Solid Solid Neoplasm Students System TP53 gene Technology Testing Therapeutic Time TimeLine Tissues Tobacco Training Translating United States United States National Institutes of Health Work anticancer research base biological adaptation to stress cancer cell experience gain of function gain of function mutation genome editing glucose metabolism in vivo insight interest loss of function mutation lung carcinogenesis lung tumorigenesis macromolecule medical schools mouse model neoplastic cell novel novel strategies oxidative damage programs research study response skills transcription factor tumor tumor initiation tumor microenvironment tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer-related deaths in the United States and worldwide (Herbst et al. 2008). Non-small-cell lung cancer (NSCLC), accounts for ~85% of all lung cancer cases. 20-30% of human NSCLC tumors acquire mutations in anti-oxidant transcription factor Nrf2 (gain-of-function (GOF)) or its negativ regulator Keap1 (LOF) suggesting an important role for oxidative stress homeostasis to maintain cancer cell survival during lung carcinogenesis. Despite the high frequency of mutations observed in this pathway, little is know about its role in lung tumor initiation and progression. To study NSCLC our laboratory utilizes a genetically engineered mouse model (GEMM) of NSCLC that faithfully recapitulates the histologic, molecular, progression features of human NSCLC. Tumors develop in the autochthonous (native) tissue context, in the presence of an intact tumor microenvironment and in the absence of confounding tobacco mutagens. I have recently developed a rapid and precise in vivo method that bypasses the need for time- consuming manipulation of the murine germline in order to engineer novel alleles of interest. I have combined the power of sophisticated Cre/loxP-based GEMMs with the highly precise genome editing CRISPR/Cas9 system. Using this powerful new approach I will functionally investigate the tumor cell- autonomous role of Nrf2 and Keap1 in the lung adenocarcinoma initiation and progression using the NSCLC GEMM. The research proposed within this application for a K22 NIH career transition award focuses on elucidating the role of the Nrf2 anti-oxidant pathway in initiation and progression by rigorous in vivo experimental approaches combining both genetic and biochemical approaches. The goals and timeline of these well-defined and achievable experiments outlined within are to: * Dissect the functional importance of Nrf2 in NSCLC tumorigenesis * Identify the metabolic changes mediated by Nrf2 in lung cancer * Identify the Nrf2 targets that are important for mediating its anti-oxidant functions in vivo * Provide a platform for experimental cross talk between observations in NSCLC GEMMs and human cell lines, which will prove valuable for future research The project described within this application has been shaped by my long-standing dedication to the field of cancer biology and more importantly my ongoing efforts in Dr. Tyler Jacks' laboratory to uncover the fundamental mechanisms involved in initiation and progression in this autochthonous mouse model of NSCLC. I have benefited from the research environment in the Jacks Laboratory, MIT, and the surrounding area that offers unmatched opportunities for scientific discussion, collaboration, and training. The scientific community at MIT, the Broad Institute, and Harvard Medical School offers countless seminars and workshops that continue to foster my scientific development. Additionally, I supervise have supervised three undergraduate MIT student, three summer students and two technical assistant that work directly with me on experiments pertaining to the proposed research project. This is an incredible experience that will endow me with many of the necessary skills to manage a laboratory during the independent phase of this award and beyond. This proposal represents my dedicated scientific investment towards identifying the fundamental drivers of NSCLC tumorigenesis, by uniting collaborators' analyses and the use of a sophisticated genetically engineered mouse. It is my intention to start an independent research program that will capitalize on the insight I obtain from the in vivo animal model with the goal to translate my findings in human systems. For the long-term, I am confident that these experiments will provide a solid foundation on which my research program can be built upon. I look forward to educating and recruiting students and postdocs that share my passion for cancer research.