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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1-CSR-M (F2))
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Rothgeb, Ann E
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Koth, Laura L; Cambier, C J; Ellwanger, Almut et al. (2010) DAP12 is required for macrophage recruitment to the lung in response to cigarette smoke and chemotaxis toward CCL2. J Immunol 184:6522-8
Woodruff, Prescott G; Ellwanger, Almut; Solon, Margaret et al. (2009) Alveolar macrophage recruitment and activation by chronic second hand smoke exposure in mice. COPD 6:86-94
Koth, Laura L; Alex, Byron; Hawgood, Samuel et al. (2007) Integrin beta6 mediates phospholipid and collectin homeostasis by activation of latent TGF-beta1. Am J Respir Cell Mol Biol 37:651-9
Woodruff, Prescott G; Koth, Laura L; Yang, Yee Hwa et al. (2005) A distinctive alveolar macrophage activation state induced by cigarette smoking. Am J Respir Crit Care Med 172:1383-92