Psoriasis is a common chronic debilitating disease of the skin, nails and joints with a major impact on the quality of life to levels comparable to those seen in cancer, diabetes and heart disease. Psoriasis is now recognized as a complex genetic disorder caused by the interaction of specific genetic components and the environment. Our knowledge of these factors has greatly accelerated over the last several years with the identification of genetic loci involved in immune and epidermal function. This includes risk variants within the gene encoding for the IL23 receptor (IL-23R) that have been shown to influence not only the risk of psoriasis but also other chronic inflammatory diseases such as ankylosing spondylitis and Crohn's disease. The ligand for the IL-23 receptor, which is composed of the IL-23R and the IL-12R21 chains, is Il-23, which has been shown to have a major pathogenic role in number of inflammatory and autoimmune diseases through its effect on interleukin-17 (Th17) and interleukin-22 (Th22) producing T-cells. The biological effects of the risk variants in the IL-23R are unknown but they lead to amino-acid changes in the cytoplasmic domain of the receptor and are therefore likely to change downstream signaling. The hypothesis of this proposal is that the risk variants within the IL-23 receptor increase the activity of the receptor with resulting changes in the activity of Th17 and Th22 cells. To address this hypothesis, ex vivo and in vitro studies will be performed to address the following Specific Aims: 1) To determine whether the IL23R risk variants influence mRNA, protein and surface expression of the IL-23R in vitro and in vivo. 2) Determine whether the IL23R risk haplotype exerts an influence on IL-23R signaling in T-cells c) To determine whether the IL23R risk haplotype leads to differences in Th17 and Th22 differentiation, expansion and/or function. Successful completion of these studies should increase our understanding of the physiological and pathological role of the common variants within the interleukin-23 receptor and provide new insights into the mechanisms of diseases where these variants play a pathogenic role.
It was recently demonstrated that coding variants in the gene for the interleukin(IL)-23 receptor increase risk of several chronic inflammatory diseases including psoriasis and Crohn's disease. IL-23 is a mediator that plays a central role in inflammatory processes but the role of these variants in its receptor and how they influence the biology of IL-23 is still unknown. The role of this project is to elucidate the physiologic role of these variants in the IL-23 receptor and provide new insights into the mechanisms of disease where these variants play a pathogenic role.
|Swindell, William R; Xing, Xianying; Voorhees, John J et al. (2014) Integrative RNA-seq and microarray data analysis reveals GC content and gene length biases in the psoriasis transcriptome. Physiol Genomics 46:533-46|
|Johnston, A; Guzman, A M; Swindell, W R et al. (2014) Early tissue responses in psoriasis to the antitumour necrosis factor-? biologic etanercept suggest reduced interleukin-17 receptor expression and signalling. Br J Dermatol 171:97-107|
|Swindell, William R; Stuart, Philip E; Sarkar, Mrinal K et al. (2014) Cellular dissection of psoriasis for transcriptome analyses and the post-GWAS era. BMC Med Genomics 7:27|
|Johnston, Andrew; Gudjonsson, Johann E (2014) Psoriasis and the MAITing game: a role for IL-17A+ invariant TCR CD8+ T cells in psoriasis? J Invest Dermatol 134:2864-6|
|Li, Bingshan; Tsoi, Lam C; Swindell, William R et al. (2014) Transcriptome analysis of psoriasis in a large case-control sample: RNA-seq provides insights into disease mechanisms. J Invest Dermatol 134:1828-38|
|Foster, Alexander M; Baliwag, Jaymie; Chen, Cynthia S et al. (2014) IL-36 promotes myeloid cell infiltration, activation, and inflammatory activity in skin. J Immunol 192:6053-61|
|Swindell, William R; Johnston, Andrew; Xing, Xianying et al. (2013) Robust shifts in S100a9 expression with aging: a novel mechanism for chronic inflammation. Sci Rep 3:1215|
|Gordon, Kristin; Kochkodan, James J; Blatt, Hanz et al. (2013) Alteration of the EphA2/Ephrin-A signaling axis in psoriatic epidermis. J Invest Dermatol 133:712-22|
|Swindell, William R; Johnston, Andrew; Voorhees, John J et al. (2013) Dissecting the psoriasis transcriptome: inflammatory- and cytokine-driven gene expression in lesions from 163 patients. BMC Genomics 14:527|
|Martin, David A; Towne, Jennifer E; Kricorian, Gregory et al. (2013) The emerging role of IL-17 in the pathogenesis of psoriasis: preclinical and clinical findings. J Invest Dermatol 133:17-26|
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