MCP-1 and TGFb in Macrophage Activation and Emphysema

描述（由申请人提供）： 该提案描述了一个为期5年的计划，用于发展肺部医学的学术生涯。 主要研究者在马萨诸塞州总医院完成了内科住院医师培训，并在加州大学旧金山分校弗朗西斯科获得奖学金，并致力于作为独立研究者的学术生涯。 该K 08计划将支持研究单核细胞趋化蛋白-1（MCP-1）在巨噬细胞调节中的作用以及肺部疾病小鼠模型中肺气肿的发展，长期目标是解决有关肺气肿发病机制的知识方面的持续空白。 整合素生物学领域的领导者大卫尔勒将指导主要研究者。 TGFa专家Dean Sheppard将担任共同导师。 该计划将招募以色列Charo和巴雷特罗林斯的专业知识，他们都是CCR 2及其配体MCP-1领域的领导者，史蒂文夏皮罗是金属蛋白酶和肺气肿小鼠模型的专家。 一个由备受尊敬的医生科学家组成的咨询委员会将提供科学和职业建议。 首席研究员还将接受教学培训，包括免疫学、细胞生物学和小鼠遗传学课程。 该项目将阐明MCP-1/CCR 2通过诱导巨噬细胞活化和MMP-12产生介导肺气肿发展的假设。 我们的中心已经证明，小鼠缺乏肺上皮细胞a？α 6整联蛋白（并且因此缺乏活化的TGF α）显示肺泡巨噬细胞活化和进行性肺气肿，这是由于巨噬细胞产生基质金属蛋白酶-12（MMP-12）。我们在该模型中的初步研究表明，MCP-1对巨噬细胞活化和MMP-12的表达至关重要。该提案的具体目标是：1）确定MCP-1和CCR 2是否需要肺气肿的发展？α 6缺陷小鼠，2）确定MCP-1和CCR 2是否是香烟烟雾诱导的肺气肿的发展所需的，和3）确定MCP-1和TGF α如何共同作用以调节巨噬细胞活化。主要研究者将在UCSF的肺部生物学中心（LBC）工作，该中心是一个国际公认的研究中心，在培训独立的学术肺部科学家方面有着出色的记录。医学系和伦敦商学院对她的职业发展以及成功完成这项工作所需的所有资源的可用性做出了全面承诺。

DESCRIPTION (provided by applicant): This proposal describes a 5-year program for the development of an academic career in Pulmonary Medicine. The principal investigator has completed Internal Medicine residency at Massachusetts General Hospital and fellowship at the University of California, San Francisco and is committed to an academic career as an independent investigator. This K08 program will support investigations into the role of monocyte chemoattractant protein-1 (MCP-1) in macrophage regulation and the development of emphysema in murine models of pulmonary disease with the long-term objective of addressing persistent gaps in knowledge about the pathogenesis of emphysema. David Erle, a leader in the field of integrin biology, will mentor the principal investigator. Dean Sheppard, an expert in TGFa, will serve as co-mentor. The program will enlist the expertise of Israel Charo and Barrett Rollins, both leaders in the field of CCR2 and its ligand, MCP-1, and Steven Shapiro, an expert in metalloproteinases and murine models of emphysema. An advisory committee of highly-regarded physician-scientists will provide scientific and career advice. The principal investigator will also pursue didactic training including courses in immunology, cell biology and mouse genetics. The proposed project will address the hypothesis that MCP-1/CCR2 mediates the development of pulmonary emphysema via induction of macrophage activation and MMP-12 production. Our center has shown that mice deficient in the lung epithelial cell a?a6 integrin (and, consequently, deficient in activated TGFa demonstrate alveolar macrophage activation and progressive emphysema that is due to macrophage production of matrix metaltoproteinase-12 (MMP-12). Our preliminary studies in this model have revealed that MCP-1 is critical for macrophage activation and the expression of MMP-12. The specific aims of the proposal are to: 1) determine whether MCP-1 and CCR2 are required for the development of emphysema in a?a6-deficient mice, 2) determine whether MCP-1 and CCR2 are required for the development of cigarette smoke-induced emphysema, and 3) determine how MCP-1 and TGFa work together to regulate macrophage activation . The principal investigator will work in the Lung Biology Center (LBC) at UCSF, an internationally recognized research center with an outstanding record of training independent academic pulmonary scientists. She has the full commitment from the Department of Medicine and LBC with regard to career development and the availability of all resources necessary for successful completion of this work.