MCP-1 and TGFb in Macrophage Activation and Emphysema

描述(由申请人提供)： 这份提案描述了一项为期5年的肺部医学学术生涯发展计划。这位首席研究员已经在马萨诸塞州综合医院完成了内科住院医师资格，并在加州大学旧金山分校获得了研究员资格，并致力于作为一名独立研究员的学术生涯。这项K08计划将支持研究单核细胞化学吸引蛋白-1(MCP-1)在巨噬细胞调节中的作用以及肺气肿在小鼠肺部疾病模型中的发展，长期目标是解决对肺气肿发病机制的长期认识空白。整合素生物学领域的领先者大卫·厄尔将指导首席研究员。TGFa专家迪恩·谢泼德将担任共同导师。该项目将征集以色列·查罗和巴雷特·罗林斯的专业知识，他们都是CCR2及其配体MCP-1领域的领导者，以及金属蛋白酶和肺气肿小鼠模型的专家史蒂文·夏皮罗。一个由备受尊敬的内科科学家组成的咨询委员会将提供科学和职业建议。首席研究人员还将继续进行教学培训，包括免疫学、细胞生物学和老鼠遗传学课程。这项拟议的项目将解决MCP-1/CCR2通过诱导巨噬细胞激活和产生基质金属蛋白酶-12而介导肺气肿发生的假说。本中心的研究表明，肺上皮细胞a？a6整合素缺乏的小鼠表现为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(MMP12)。我们在这个模型中的初步研究表明，MCP-1对巨噬细胞的激活和基质金属蛋白酶-12的表达至关重要。该提案的具体目的是：1)确定MCP-1和CCR2是否对A6缺陷小鼠的肺气肿的发生起作用；2)确定MCP-1和CCR2是否对香烟烟雾诱导的肺气肿的发生起作用；以及3)确定MCP-1和TGFa如何共同调节巨噬细胞的激活。首席研究员将在加州大学旧金山分校的肺生物学中心(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。她得到了医学部和LBC在职业发展和成功完成这项工作所需的所有资源方面的充分承诺。

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.