The overall objective of the Program is to characterize important host regulatory mechanisms and signaling pathways that govern the induction and regulation of innate and acquired mucosal immune and inflammatory responses in the intestinal tract to enteric microbes and their products. The Program is designed with 4 Research Units and 4 Cores. Three Research Units and all 4 Cores are currently funded through 6/30/2014. This supplementary application requests a change in the research goals and Project Leader of Research Unit 4, as initially submitted and funded, for the 3 year period 7/01/2011-6/30/2014. The proposed Project leader for replacement Research Unit 4 is Dr. Michael Karin, who has a proven record of being highly interactive with the 3 other Research Unit leaders. A revised Research Unit 4, under Dr. Karin's leadership, will greatly enhance the ability of the Program to achieve maximum productivity focused on its overall objectives. Dr. Karin's project """"""""Role of I?B kinase subunits in mucosal immune homeostasis"""""""" has 4 aims that are closely aligned and integrated with the 3 ongoing Research Units. Research Unit 4, as proposed, is highly innovative and uses state-of-the-art approaches to address the important roles and mechanisms by which IKKa and IKK? regulate intestinal mucosal homeostasis and inflammation. This Unit will interact extensively with Research Unit 1 that investigates the regulation of mucosal innate immune responses by dendritic cells (DC) and epithelial cells in the colon and small intestine using an attaching and effacing lesion inducing enteric pathogen and rotavirus to probe the host response, with Research Unit 2 that investigates intestinal mucosal responses that determine immune defenses against the minimally invasive enteric pathogen Giardia, which elicits strong protective immunity in the absence of mucosal inflammation, and with Research Unit 3 that investigates how mucosal adjuvants override the tolerance-inducing effects of T regulatory cells and provoke effector T cell immune responses, with a focus on cholera toxin and Th17 differentiation. The research projects are supported by four Cores: a Mouse Model Core, a Histopathology Core, an Imaging and Cell Sorting Core and an Administrative Core.
The Intestinal mucosa is a major site of interaction between the host and enteric pathogens that cause diarrheal illness, morbidity and death among millions worldwide each year. These studies will elucidate mechanisms and pathways that determine how the host responds to infection with enteric microbes. We anticipate this research will result in the identification of cellular and molecular targets that can be used and manipulated to achieve more effective host protective immunity to enteric infections through pharmacological, molecular, cellular and vaccine interventions.
|Bertin, Samuel; Aoki-Nonaka, Yukari; Lee, Jihyung et al. (2017) The TRPA1 ion channel is expressed in CD4+ T cells and restrains T-cell-mediated colitis through inhibition of TRPV1. Gut 66:1584-1596|
|Lakhdari, Omar; McAllister, Christopher S; Wang, Michael et al. (2016) TLR3 signaling is downregulated by a MAVS isoform in epithelial cells. Cell Immunol 310:205-210|
|Solaymani-Mohammadi, Shahram; Lakhdari, Omar; Minev, Ivelina et al. (2016) Lack of the programmed death-1 receptor renders host susceptible to enteric microbial infection through impairing the production of the mucosal natural killer cell effector molecules. J Leukoc Biol 99:475-82|
|de Jong, Petrus R; Taniguchi, Koji; Harris, Alexandra R et al. (2016) ERK5 signalling rescues intestinal epithelial turnover and tumour cell proliferation upon ERK1/2 abrogation. Nat Commun 7:11551|
|Dann, Sara M; Manthey, Carolin F; Le, Christine et al. (2015) IL-17A promotes protective IgA responses and expression of other potential effectors against the lumen-dwelling enteric parasite Giardia. Exp Parasitol 156:68-78|
|Wang, Kepeng; Karin, Michael (2015) The IL-23 to IL-17 cascade inflammation-related cancers. Clin Exp Rheumatol 33:S87-90|
|Bertin, S; Lozano-Ruiz, B; Bachiller, V et al. (2015) Dual-specificity phosphatase 6 regulates CD4+ T-cell functions and restrains spontaneous colitis in IL-10-deficient mice. Mucosal Immunol 8:505-15|
|Vicente-Suarez, I; Larange, A; Reardon, C et al. (2015) Unique lamina propria stromal cells imprint the functional phenotype of mucosal dendritic cells. Mucosal Immunol 8:141-51|
|de Jong, P R; Takahashi, N; Peiris, M et al. (2015) TRPM8 on mucosal sensory nerves regulates colitogenic responses by innate immune cells via CGRP. Mucosal Immunol 8:491-504|
|de Jong, Petrus R; Takahashi, Naoki; Harris, Alexandra R et al. (2014) Ion channel TRPV1-dependent activation of PTP1B suppresses EGFR-associated intestinal tumorigenesis. J Clin Invest 124:3793-806|
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