This is an application for a Texas Medical Center NIH/NIAID Asthma and Allergic Diseases Cooperative Research Center that unites the University of Texas M.D. Anderson Cancer Center and Baylor College of Medicine to investigate the role of human Thymic Stromal Lymphopoietin (TSLP) in the development and maintenance of the Th2 immune response that dominates the allergic phenotype. The proposed studies will test the overall hypothesis that TSLP is a master switch for developing and maintaining atopy and asthma. TSLP is a hematopoietic cytokine encoded on the human chromosome 5q22 cluster of Th2 cytokine genes, and in humans is produced predominately by epithelial cells and activated mast cells, and is expressed in the context of atopic dermatitis and allergic asthma. Genetically engineered murine models of allergic disease also support a central role for TSLP in the pathobiology of atopy. This proposal integrates four research projects, two research cores and an administrative core focused on TSLP. Project 1 will investigate the mechanisms for induction of TSLP expression by human respiratory epithelial cells and mast cells. Project 2 will determine the mechanisms by which TSLP activates myeloid dendritic cells. Project 3 will elucidate mechanisms by which TSLP activated myeloid dendritic cells propagate Th2 effecter and memory cells. Project 4 will focus on the role of inflammatory T helper cells (Thi) in the upregulation of TSLP production. These projects will be supported by an Administrative Core, an Analytical Research Core, and a Clinical Research Core. The proposed studies should provide new insight into the mechanisms of allergic disease and asthma, and potentially identify new targets for therapeutic intervention. PROJECT 1: Regulation of TSLP Expression (Huston, D.) DESCRIPTION (provided by applicant): This application for a Texas Medical Center AADCRC is an inter-disciplinary, inter-institutional, highly integrated program focused on elucidating the role of human Thymic Stromal Lymphopoietin (TSLP) in the development and maintenance of the Th2 immune response that dominates the allergic phenotype. Preliminary data support an innate and adaptive two-stage model for TSLP-mediated allergic inflammation. Four integrated Projects and three Cores are proposed to investigate the overall hypothesis that TSLP is a master switch for developing and maintaining the allergic phenotype. Project 1 is focused on mechanisms regulating the expression of TSLP; Project 2 is focused on TSLP activation of myeloid dendritic cells (mDC); Project 3 is focused on mDC propagation of Th2 immunity; and Project 4 is focused on T cell feedback regulation on TSLP expression. Project 1 will test the hypothesis that aeroallergens and respiratory viral pathogens linked to atopy and allergic asthma can stimulate respiratory epithelial cells and mast cells to produce TSLP, and thereby initiate the innate immunologic cascade for allergic inflammation.
Aim 1 will investigate the hypothesis that respiratory syncytial virus (RSV), rhinovirus (RV), and aeroallergens induce expression of TSLP by human respiratory epithelial cells and mast cells, in vitro.
Aim 2 will investigate the hypothesis that upregulation of TSLP expression in human respiratory epithelial cells and mast cells, utilizes NF?B, AP-1, and STAT6 activation pathways.
Aim 3 will investigate the in vivo effects of RSV, RV, and aeroallergens to induce expression of TSLP in patients with and without allergic rhinitis and asthma. Proposed studies will utilize established techniques for: (i) measuring TSLP by real-time PCR, in situ hybridization, immunohistology, ELISA, and bioassays; (ii) culture and analysis of human primary bronchial and nasal epithelial cells, bronchial epithelial cell lines, CD34- derived mast cells, and the LAD2 mast cell line; (iii) RSV and RV expertise through the BCM-NIH Viral Respiratory Pathogens Research Unit; (iv) analysis of nuclear gene activation, using promoter-luciferase constructs; and (v) Clinical Research studies with available patients with and without allergic rhinitis and asthma. Studies will utilize and leverage the expertise in all three Cores. The proposed studies will provide insight into the pathogenic mechanisms of allergic inflammation and define novel targets for developing innovative therapies for allergic asthma and atopy.
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