Regulation of Human Mast Cell Function

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DESCRIPTION (provided by applicant): The long-term goal is for Dr. Zhao to develop as an independent physician scientist with the skill and maturity to identify research opportunities and to construct rationale and achievable strategies to address these opportunities. The combination of advanced coursework and mentoring should make this possible. Dr. Lawrence B. Schwartz will serve as mentor. Dr. Zhao recently joined the VCU as an Assistant Professor of Pediatrics beginning July, 2003. Research space has been provided within the Department of Pediatrics along with salary support and protected time. Human mast cells are effector cells of acquired and probably innate immunity. They are abundant around blood vessels and in cutaneous, gastrointestinal and pulmonary tissues. The ability to obtain human skin-derived mast cells of high purity that proliferate in culture and retain the functional phenotype of the original mast cells provides a critical tool for research on such ceils. The current proposal will examine relationships between these mast cells and cytokines, and the role of such mast cells in the pathogenesis of chronic urticaria. Aim 1 will characterize the cytokines and lipid mediators produced by human skin-derived mast cells activated through FcepsilonRI. Because preliminary results indicate many of the cytokines are degraded during or shortly after their release, presumably by co-released mast cell proteases, conditions will be developed to prevent their degradation and thereby appreciate the full extent of their production. Aim 2 will examine the ability of cytokines to regulate cytokine production and prostaglandin and leukotriene generation by mast cells activated through IgE and IgG receptors. Aim 3 will characterize the ability of sera from patients with chronic urticaria to label the surface of and to activate or prime human skin-derived mast cells. Understanding these functional attributes of human mast cells will provide insights into the pathogenesis of allergic disease and may reveal new therapeutic targets.