The Role of PPARgamma in Lung Cancer Progression and Metastasis

PPARγ 在肺癌进展和转移中的作用

• 批准号: 8970678
• 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
• 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/8970678
• 关键词: 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; mid-career faculty; 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

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）： 该建议描述了一项为期5年的培训计划，以开发肺癌研究的学术生涯。申请人于2010年在科罗拉多大学丹佛大学完成了结构化的肺和重症监护奖学金，现在将扩大他的科学技能，以发展为独立的研究者。 该计划将扩展我们对肺癌进展和转移的了解。罗伯特·基思（Robert Keith）博士将指导申请人的科学发展。基思博士是肺癌领域的知名研究员，尤其是在肺癌化学预防方面。他是丹佛VA医疗中心研究与开发的参谋长。为了增强培训，该计划将招募医学教授拉斐尔·尼梅诺夫（Raphael Nemenoff）博士，肺癌研究领域的公认领导者，尤其是在肿瘤微环境方面；以及在发展体内动物模型方面拥有丰富经验的医学副教授Mary Weiser-Evans博士。此外，由备受瞩目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的作用上，PPARY是配体激活转录因子的核受体超家族，在肺癌进展和转移中的成员。 Nemenoff博士实验室的最新工作表明，用吡格列酮治疗小鼠，这是一种药理学促进剂，可以加速肺癌转移。 Nemenoff实验室和其他人的先前工作表明，癌细胞中PPARY的激活促进了分化并抑制了转化的生长。因此，我们假设用吡格列酮治疗会导致肿瘤微环境中细胞中PPARY的激活，例如肿瘤相关的巨噬细胞，从而加速了肺癌转移。具体目的包括：1）确定全身性PPARY激活对肺癌进展和转移的影响，2）评估巨噬细胞中PPARY选择性缺失对转移的影响的影响，3）建立巨噬细胞特异性PPARY在介导癌细胞与癌细胞之间的相互作用中的作用。如果吡格列酮（是硫代二酮类抗糖尿病剂的成员，确实会加速转移，那么对当前处方的噻唑烷二酮的糖尿病患者可能会有深远的影响。 丹佛VA医学中心以及科罗拉多大学丹佛分校的肺科学和重症监护医学部，通过将各种资源的专业知识纳入定制计划中，为培训医师科学家提供了理想的环境。这种环境最大程度地提高了申请人建立科学利基市场的潜力，可以从中建立学术职业。