UPREGULATION OF 5-LIPOXYGENASE IN ALVEOLAR MACROPHAGES

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Applicant: The applicant is a Lecturer in Internal Medicine who has demonstrated an aptitude for original investigation both in clinical and basic science research. These clinical studies and basic science investigations have been published in high quality peer review journals. He is committed to a research career in basic pulmonary biology and devotes 80% of his effort to research activity and seeks the Clinical Investigator Development Award to support his development into an independent investigator. Environment: The Division of Pulmonary and Critical Care Medicine and Medical School at the University of Michigan provide an exceptional scientific environment. The extraordinary support and expertise of the applicant's sponsor (Dr. Marc Peters-Golden), the extensive experience of the members of my training committee (Drs. Galen Toews, Dr. Joseph Fantone and David Ginsburg), and consultation with a basic scientist expert in the area of 5-lipoxygenase (5-LO) activation, (Dr. Jilly Evans), will help ensure the successful execution of the proposal and the investigative growth of the applicant during the term of the Clinical Investigator Development Award. Research: 5-LO metabolites play an important role in pulmonary inflammation. Given that alveolar macrophages (AM) exhibit an unusually high capacity for the synthesis of leukotrienes (LT), the applicant has studied the regulation of 5-LO in AM. The goal of the present proposal is to elucidate the molecular mechanisms by which 5-LO metabolism in AM is upregulated. Based on the finding that cultured AM exhibit a time- dependent decline in 5-LO capacity, the general hypothesis is that the constituents in the alveolar environment upregulate 5-LO metabolism as monocytes differentiate into AM within the lung. The specific hypothesis is that alterations in the amount and function of 5-LO and FLAP proteins account for the upregulation of 5-LO in AM. Initially, rat AM will be studied in culture and the time-dependent decline in LT synthesis correlated with changes in mechanisms regulating 5-LO metabolism. The specific aims are to determine whether decreased 5-LO capacity in AM, removed from the alveolar space, is associated with: 1) qualitative or quantitative alterations in 5-LO and or FLAP proteins; and 2) functional alterations in 5-LO and FLAP activities. Specific aim 3) is to determine if alveolar lining fluid is responsible for the increased 5-LO capacity of AM, by its ability to prevent the reduction of 5-LO metabolism in cultured AM over time. If 5-LO metabolism can be upregulated, specific aim 4) is to determine if alveolar lining fluid is capable of directly upregulating LT synthesis in monocytes and altering the mechanisms of 5-LO activation to resemble those of AM. These studies should enhance our basic understanding of macrophage 5-LO regulation in general and specifically in the lung. Eventually they may lead to new approaches for the modulation of inflammatory and immunologic pulmonary disease.