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The Role of PPARgamma in Lung Cancer Progression and Metastasis

PPARγ 在肺癌进展和转移中的作用

基本信息

批准号：
8444259
负责人：
Howard Li
金额：
--
依托单位：
VA EASTERN COLORADO HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8444259
关键词：
2,4-thiazolidinedione Advisory Committees Agonist Animal Model Animals Antidiabetic Drugs Atherosclerosis Blood Vessels Bone Marrow Brain Cancer Etiology Cancer cell line Cause of Death Cells Cessation of life Coculture Techniques Colorado Control Animal Critical Care Data Detection Development Diabetes Mellitus Diagnosis Disease Distant Environment Event Fellowship Fibroblasts Growth Human Immune Immunocompetent In Vitro Incidence Inflammatory Knowledge Laboratories Lead Ligands Liver Lung Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediastinal lymph node group Mediating Medical Medical center Medicine Mentors Methods Modeling Molecular Mus Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Nuclear Receptors Nude Mice Organ PPAR gamma Patients Peroxisome Proliferator-Activated Receptors Phenotype Physicians Pioglitazone Population Primary Neoplasm Program Development Reporting Research Research Personnel Resources Retrospective Studies Role Science Scientist Spatial Distribution Stromal Cells Stromal Neoplasm Structure Thiazolidinediones Time Training Training Programs United States Universities Veterans Wild Type Mouse Work Xenograft Model activating transcription factor anticancer research cancer cell cancer chemoprevention cancer risk career cell type diabetic experience feeding in vivo lung tumorigenesis macrophage member migration mouse model neoplastic cell new therapeutic target novel preclinical study prevent professor programs research and development research study response skills tumor tumor growth tumor initiation tumor microenvironment tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for the development of an academic career in lung cancer research. The applicant completed a structured Pulmonary and Critical Care fellowship at the University of Colorado Denver in 2010, and will now expand his scientific skills to develop into an independent investigator. This program will extend our knowledge of lung cancer progression and metastasis. Dr. Robert Keith will mentor the applicant's scientific development. Dr. Keith is an established researcher in the field of lung cancer, especially with regards to lung cancer chemoprevention. He is the Associate Chief of Staff for Research and Development at the Denver VA Medical Center. To enhance the training, the program will enlist the expertises of Dr. Raphael Nemenoff, Professor of Medicine and a recognized leader in the field of lung cancer research, especially with regards to the tumor microenvironment; and Dr. Mary Weiser-Evans, an Associate Professor of Medicine with extensive experience in developing in vivo animal models. In addition, an advisory committee of highly-regarded medical scientists will provide scientific and career advice. Research will focus on the role of PPARy, which is a member of the nuclear receptor superfamily of ligand-activated transcription factors, in lung cancer progression and metastasis. Recent work in the laboratory of Dr. Nemenoff has shown that treating mice with pioglitazone, which is a pharmacological PPARy activator, accelerates lung cancer metastasis. Previous work from the Nemenoff laboratory and others has shown that activation of PPARy in cancer cells promotes differentiation and inhibits transformed growth. Thus, we hypothesize that treatment with pioglitazone leads to activation of PPARy in cells in the tumor microenvironment, such as tumor-associated macrophages, which accelerates lung cancer metastasis. The specific aims include: 1) determine the effect of systemic PPARy activation on lung cancer progression and metastasis, 2) assess the effect of selective deletion of PPARy in macrophages on metastasis, and 3) establish the role of macrophage-specific PPARy in mediating interactions between cancer cells and macrophages. If pioglitazone, which is a member of the thiazolidinedione class of antidiabetic agents, indeed accelerates metastasis, then there may be far-reaching implications for diabetics currently being prescribed thiazolidinediones. The Denver VA Medical Center and the Division of Pulmonary Sciences and Critical Care Medicine at the University of Colorado Denver provide an ideal setting for training physician-scientists by incorporating expertise from diverse resources into customized programs. Such an environment maximizes the potential for the applicant to establish a scientific niche from which an academic career can be constructed.

描述(由申请人提供)：这份提案描述了一项为期5年的培训计划，旨在发展肺癌研究的学术生涯。申请者于2010年在科罗拉多丹佛大学完成了结构化的肺和重症护理奖学金，现在将扩大他的科学技能，发展成为一名独立的调查人员。这个项目将扩大我们对肺癌进展和转移的了解。罗伯特·基思博士将指导申请者的科学发展。基思博士是肺癌领域的知名研究人员，尤其是在肺癌化学预防方面。他是丹佛退伍军人医学中心负责研究和开发的副参谋长。为了加强培训，该计划将招募拉斐尔·内门诺夫博士和Mary Weiser-Evans博士，前者是医学教授，也是肺癌研究领域的公认领导者，特别是在肿瘤微环境方面；Mary Weiser-Evans博士是医学副教授，在开发活体动物模型方面具有丰富经验。此外，一个由备受尊敬的医学科学家组成的咨询委员会将提供科学和职业建议。研究将集中在PPARy，它是配体激活的转录因子核受体超家族的成员，在肺癌进展和转移中的作用。涅门诺夫博士的实验室最近的工作表明，用吡格列酮治疗小鼠，这是一种药理上的PPARy激活剂，会加速肺癌的转移。奈门诺夫实验室和其他实验室之前的工作表明，癌细胞中PPARy的激活促进了分化，抑制了转化生长。因此，我们假设，吡格列酮治疗导致肿瘤微环境中的细胞，如肿瘤相关巨噬细胞，激活PPARy，从而加速肺癌转移。其具体目的包括：1)确定系统PPARy激活对肺癌进展和转移的影响，2)评估巨噬细胞中选择性缺失PPARy对转移的影响，以及3)建立巨噬细胞特异性PPARy在介导癌细胞和巨噬细胞之间相互作用中的作用。如果吡格列酮，这类抗糖尿病药物中的一员，确实加速了转移，那么对目前正在服用噻唑烷二酮类药物的糖尿病患者可能会有深远的影响。丹佛退伍军人医学中心和科罗拉多大学丹佛大学肺科学和重症监护医学部通过将来自不同资源的专业知识整合到定制项目中，为培训内科科学家提供了理想的环境。这样的环境最大限度地增加了申请者建立一个科学利基的潜力，在这个利基上可以建立一个学术生涯。