Molecular Mechanisms Leading to Human Asthma

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DESCRIPTION (Applicant?s Abstract) Asthma is a chronic inflammatory syndrome whose common pathobiological expression is inflammation. The causes for asthma are unknown, and it is generally accepted that asthma results from an interaction between environmental and genetic factors. However, very little is known of genes that contribute to asthma. It is the goal of this SCOR to use a genetic approach to identify genes that influence mechanisms leading to the development of asthma. In addition, we will study basic mechanisms that may contribute to the asthmatic phenotype. The proposed SCOR in asthma consists of four scientific projects, with one of the projects serving as the clinical component. Each of these projects will dissect pathways with established relevance to human asthma and will functionally evaluate genetic polymorphisms that have already been identified that may impact these pathways. Project 1: Fine mapping, and testing of candidate genes. The goal of this project is to fine map Asthma candidate genes on 12Q and to provide a population-based resource for projects 2-4 to test candidate genes in molecular pathways. Project 2: Molecular regulation of cytokine (IL-4 and INFgamma) gene expression. The cytokines IL-4 and INFgamma both have critical roles in the development of asthma. Importantly, a polymorphism in the intronic region of the INFgamma gene has been linked to a genetic predisposition for asthma. The goal of this project is to explore the different roles of NFAT proteins in regulating IL-4 gene transcription and to investigate the regulation of INFgamma gene expression, determining if the known polymorphism impacts INFgamma gene transcription. Proiect 3: Cytokine (IL-4 and IL-13) responses in human airway smooth muscle cells. The cytokines IL-4 and IL-13 have been implicated as important in the development of allergic asthma. The goal of this project is to specifically address the role of these cytokines on cultured human airway smooth muscle cells. Importantly, the relevance of known polymorphisms in the IL-4 and IL-13 receptors will be addressed. Project 4: Regulation of IgE receptor expression and function. The IgE/FceRI network plays a central role in allergic inflammation. IgE regulates FceRI expressior that in turn regulates FceRI mediated effector functions. The goal of this project is to dissect the process of IgE-mediated FceRI expression at the molecular level with a special emphasis placed on understanding the role of the receptor beta gene in this process. Specifically, the impact of known polymorphisms in the beta gene that are associated with asthma and atopy will be assessed. Taken together, the basic science projects combined with the clinical component in this SCOR will result in an increased understanding of mechanisms that contribute to the onset of asthmatic disease. It is hoped that these combined investigations in this SCOR will provide a platform for further gene discoveries and functional evaluations relevant to asthma.