Microtubules are complex organelles which are involved in a number of cellular functions, including the regulation of cytokine production. Presently, little is known about the composition and function of microtubules in mononuclear phagocytes, about the role of microtubules during the mononuclear phagocyte's inflammatory response, or about the mechanism by which microtubules are involved with the production of cytokines, such as interleukin-1beta and tumor necrosis factor-alpha. This Clinical Investigator Award proposal will provide important new information regarding monocyte and alveolar macrophage microtubules at rest and during inflammation. The award will commence at the completion of the candidate's third year as a Parker B. Francis Fellow in Pulmonary Research and provide support for the first five years as a junior faculty member. The candidate is unequivocally committed to a career in academic research; this award will provide a foundation for a career as an independent investigator in pulmonary cell biology. The proposal has three major objectives: (1) to investigate differences in the composition of microtubules during various stages of mononuclear phagocyte differentiation and during mononuclear phagocyte activation, (2) to determine the mechanism by which microtubular proteins affect interleukin-1beta and tumor necrosis factor-alpha production, and (3) to obtain didactic instruction to facilitate these studies and to provide a solid background in protein biochemistry and molecular biology for further career development in clinical research. This proposal integrates the pulmonary clinical research expertise of the sponsors, Dr. Mark Wewers and Dr. James Gadek, with the basic science expertise of three faculty members from the Departments of Molecular Genetics, Cell Biology, and Pharmacy at the Ohio State University. These advisors are all actively studying different aspects of microtubule structure and function. This unique combination of support provides the ideal environment for the developing clinical investigator. Furthermore, the studies planned will result in a clearer picture of cytokine production in response to inflammatory stimuli and will result in a better understanding of the relatively under-investigated area of the role of microtubules in lung disease and sepsis.
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