Emphysema attenuation via modulation of macrophage NFKB and antiprotease activity

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DESCRIPTION (provided by applicant): As a physician-scientist, my overarching career goal is to use the tools available to me in the research setting to work towards treatments for the lung diseases that I encounter in the clinical arena. I plan to become an independent principal investigator in an academic division of pulmonary medicine and to spend approximately 80% of my time pursuing scientific research. Patient care and teaching responsibilities as a pulmonary and critical care attending will occupy the remainder of my time and help to keep me focused on the diseases that drive our research efforts. I plan to use the K08 award to build upon my initial work on lentiviral manipulation of alveolar macrophages and the role that these cells play in emphysema pathogenesis. During this time, I plan to develop my research career by: 1) laying an educational foundation in immunology through a combination of formal coursework and regular attendance at a weekly pulmonary immunology conference to discuss my research and that of others; 2) expanding my technical repertoire to include additional skills central to a career in molecular biology research; 3) using the assets acquired in numbers 1 and 2 above to extend and broaden my work to date; and 4) transitioning from a mentored research environment to one of independent scientific inquiry. Patients with alpha-1 antitrypsin (AAT) deficiency have decreases in circulating blood and lung epithelial lining fluid AAT that ultimately lead to panacinar emphysema, particularly in the setting of cigarette smoke exposure. Current therapy for patients with impaired lung function resulting from AAT deficiency is replacement via weekly infusions of AAT from pooled human plasma.4 This treatment is expensive, inefficient (only a small fraction of the infused AAT reaches the lung),5 and involves a lifetime of exposure to human blood products and the risks that accompany such exposure. A comprehensive understanding of AAT biology is lacking and has been a major barrier to development of new treatments for AAT deficient patients. Although it has long been known that AAT functions to inactivate neutrophil elastase in the lung, it has only recently been recognized to have a variety of alternative and significant biological effects. In particular, the effects that AAT exerts on signaling of the key transcription factor nuclear factor-kB (NF-kB) are not well understood. The goals of this proposal are first, to better understand the relationship between AAT and NF-kB to help further our knowledge of emphysema pathogenesis; and second, to test a potential gene therapy for AAT deficiency based on local expression of the normal human AAT protein in the alveolar macrophage (AM), the cell type most implicated in lung destruction in AAT deficient patients. To accomplish these goals, the investigators have developed a new tool allowing tracking of NF-kB activity in live animals, something that was not previously possible. The experiments outlined further develop this tool and then use it to help test whether anti-inflammatory effects exerted by AAT in the lung are accompanied by suppression of NF-:B translocation and additionally whether AAT deficiency is characterized by chronic activation of NF-:B signaling. They test the effects of manipulating NF-:B signaling in the setting of cigarette smoke exposure. They then proceed to test whether or not life-long overexpression of AAT in resident AMs ameliorates emphysema via anti-inflammatory effects characterized by suppression of macrophages NF-:B activation in normal or AAT deficient mice. PUBLIC HEALTH RELEVANCE: Alpha-1 antitrypsin (AAT) deficiency is one of the most common hereditary lung diseases world-wide. Findings helping to explain how AAT protects the lung in the setting of injury are therefore likely to have great significance. Any novel treatment capable of affecting progression of emphysema will similarly have a significant long-term clinical impact.