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: 8803265
• 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/8803265
• 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; 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）： 该提案描述了一项为期 5 年的肺癌研究学术职业发展培训计划。申请人于 2010 年在科罗拉多大学丹佛分校完成了结构化的肺部和重症监护奖学金，现在将扩展他的科学技能，以发展成为一名独立研究者。 该计划将扩展我们对肺癌进展和转移的了解。罗伯特·基思博士将指导申请人的科学发展。 Keith 博士是肺癌领域的知名研究员，特别是在肺癌化学预防方面。他是丹佛退伍军人医疗中心负责研发的副参谋长。为了加强培训，该项目将聘请医学教授、肺癌研究领域公认的领导者 Raphael Nemenoff 博士的专业知识，特别是在肿瘤微环境方面； Mary Weiser-Evans 博士是医学副教授，在开发体内动物模型方面拥有丰富的经验。此外，由备受推崇的医学科学家组成的咨询委员会将提供科学和职业建议。 研究将重点关注 PPARγ（配体激活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。 Nemenoff 博士实验室最近的研究表明，用吡格列酮（一种 PPARγ 药理激活剂）治疗小鼠可加速肺癌转移。 Nemenoff 实验室和其他人之前的工作表明，癌细胞中 PPARγ 的激活可促进分化并抑制转化生长。因此，我们假设吡格列酮治疗会导致肿瘤微环境中细胞（例如肿瘤相关巨噬细胞）中 PPARγ 的激活，从而加速肺癌转移。具体目标包括：1) 确定全身 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删除 PPARy 对转移的影响，3) 确定巨噬细胞特异性 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（噻唑烷二酮类抗糖尿病药的一员）确实能加速转移，那么对目前服用噻唑烷二酮类药物的糖尿病患者可能会产生深远的影响。 丹佛退伍军人医疗中心和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不同资源的专业知识融入定制项目，为培训医师科学家提供了理想的环境。这样的环境最大限度地发挥了申请人建立科学利基的潜力，并以此为基础构建学术生涯。