Interactions between the host innate immune system and the enteric microbiota are proximal events in the pathogenesis of the idiopathic human inflammatory bowel diseases (IBD). Solving the pathogenesis of IBD and ultimately curing and preventing these chronic, debilitating conditions depends on using experimental models and human systems to better understand functional interactions between innate immunity and enteric microbes that determine differentiation and activation of effector vs. regulatory T cell subsets in mucosal tissues. We hypothesize that subsets of the commensal microbiota preferentially activate protective vs. destructive innate signaling pathways that integratively activate mucosal innate and antigen presenting cells to secrete cytokines that promote regulatory vs. effector T cell responses. These interacting bacterially- activated innate and adaptive pathways mediate homeostatic vs. effector immune responses and can be manipulated for therapeutic purposes. This hypothesis will be addressed through synergistic efforts of six fully integrated investigators with complementary expertise in innate immunity and host-microbiota interactions, facilitated by two highly utilized cores. Project 1 (Jenny Ting): """"""""NOD-like receptors in intestinal inflammation"""""""". Project 2 (Balfour Sartor): """"""""Role of IL-10 in APC regulation of protective vs. pathogenic T cell responses to commensal bacteria"""""""". Project 3 (Scott Plevy): """"""""Macrophage IL-10 and IL-12 regulation by the enteric microbiota in intestinal inflammation """""""". Project 4 (John Rawls): """"""""Microbial regulation of systemic neutrophil function"""""""". The Project Leaders will be supported by two highly interactive cores that have already facilitated collaborative research. Core A: Gnotobiotic and Transgenic Rodent and Zebrafish Core (Core Co- Directors, Drs. Sartor and Rawls). Core B: Human Tissue and Genomics Core (Co-Directors, Drs. Scott Plevy, Hans Herfarth and Shehzad Sheikh). The investigators, facilitated by Cores, are poised to accelerate the understanding of how the innate immune system interacts with the enteric microbiota in health and disease. This knowledge could have a major public health impact upon IBD and the numerous disorders that result from dysregulated innate immune interactions with enteric microbiota.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK094779-02
Application #
8737236
Study Section
Special Emphasis Panel (ZDK1-GRB-6 (M1))
Program Officer
Perrin, Peter J
Project Start
2013-09-19
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
$1,515,537
Indirect Cost
$381,836
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Huang, Juin-Hua; Liu, Chu-Yu; Wu, Sheng-Yang et al. (2018) NLRX1 Facilitates Histoplasma capsulatum-Induced LC3-Associated Phagocytosis for Cytokine Production in Macrophages. Front Immunol 9:2761
Weiser, Matthew; Simon, Jeremy M; Kochar, Bharati et al. (2018) Molecular classification of Crohn's disease reveals two clinically relevant subtypes. Gut 67:36-42
Cronan, Mark R; Matty, Molly A; Rosenberg, Allison F et al. (2018) An explant technique for high-resolution imaging and manipulation of mycobacterial granulomas. Nat Methods 15:1098-1107
Ellermann, Melissa; Sartor, R Balfour (2018) Intestinal bacterial biofilms modulate mucosal immune responses. J Immunol Sci 2:13-18
Pushalkar, Smruti; Hundeyin, Mautin; Daley, Donnele et al. (2018) The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression. Cancer Discov 8:403-416
Truax, Agnieszka D; Chen, Liang; Tam, Jason W et al. (2018) The Inhibitory Innate Immune Sensor NLRP12 Maintains a Threshold against Obesity by Regulating Gut Microbiota Homeostasis. Cell Host Microbe 24:364-378.e6
Vázquez-Baeza, Yoshiki; Gonzalez, Antonio; Xu, Zhenjiang Zech et al. (2018) Guiding longitudinal sampling in IBD cohorts. Gut 67:1743-1745
Ho, G-T; Aird, R E; Liu, B et al. (2018) MDR1 deficiency impairs mitochondrial homeostasis and promotes intestinal inflammation. Mucosal Immunol 11:120-130
Keith, Benjamin P; Barrow, Jasmine B; Toyonaga, Takahiko et al. (2018) Colonic epithelial miR-31 associates with the development of Crohn's phenotypes. JCI Insight 3:
Sartor, R Balfour; Wu, Gary D (2017) Roles for Intestinal Bacteria, Viruses, and Fungi in Pathogenesis of Inflammatory Bowel Diseases and Therapeutic Approaches. Gastroenterology 152:327-339.e4

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