Unraveling the molecular mechanisms which promote the development of asthmatic inflammation represents one of the most challenging and important areas that need to be elucidated in order to understand this disease. We hypothesize that interactions between the innate and adaptive immune systems alter airway cells in a manner that promotes the initiation and propagation of the chronic airway inflammation associated with the differing asthmatic phenotypes. The individual projects in this program examine a diverse group of mediators, cytokines, chemokines, and airway cells. Each project will, however, relate to the central theme and share substantial commonality in the molecular mechanisms to be studied. Project 1 will define the molecular events that determine the outcome of differentiation of naive or uncommitted T cells to T helper (Th)1 or Th2 cells, and the relation of this process to the asthma phenotype. Project 2 will investigate the mechanisms underlying the novel observation that galectins stimulate chemotaxis of eosinophils and mononuclear phagocytes, possibly through direct binding to chemokine receptors. Project 3 will examine the regulatory mechanisms of lipopolysaccharide (LPS) on cytokine/chemokine synthesis in alveolar macrophages, highlighting the role of the Toll-like receptor 4 (TLR4) and its downstream signaling pathways. Project 4 will define the in vivo mechanisms by which kinins stimulate expression of chemokines and chemokine receptors in human airway epithelial cells, thereby focusing the recruitment of inflammatory cells to the airway. Three Cores are proposed for this Asthma and Allergic Diseases Research Center (AADRC): an Administrative Core A, a Clinical Core B, and an Animal Core C. A major strength of this Program Project will be the experimental design of sharing samples (bronchial biopsy and bronchoalveolar fluid) from each subject among all four projects, allowing the diverse results to be combined into a comprehensive analysis of the asthmatic phenotype. This AADRC program is designed to leverage diverse expertise, resources, and experimental targets into a focused investigation of the origins of asthmatic inflammation. Taken together these projects may characterize key molecular mechanisms that contribute to the subsequent chronic inflammatory airway milieu that is the hallmark of the asthmatic phenotype. Efforts to elucidate and then modify key events leading to asthmatic inflammation may ultimately be exploited for prevention of asthmatic disease.
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