The overarching theme of the current program project grant is to define how the innate immune system informs the adaptive immune system in the intestine and how miscommunication in this interaction results in the development of IBD. Our currently funded grant has a strong emphasis on the role of the lEC in regulating innate and adaptive Immune responses in health and disease. While the epithelial cell will continue to be a prominent focus in this renewal, the data generated thus far have allowed the projects to evolve in the direction of studying the regulation of Th17 responses, a key cell type involved in mucosal inflammation. All projects have aims that involve the use of mouse and human models allowing the investigators to make observations in human tissues that can then be modeled in the mouse and vice versa (results obtained through the study of animal models can be validated by studying human tissues). In the first project the focus is on assessing the role of a newly defined population that expresses both FoxP3 and IL-17 in Crohn's disease tissues and may represent the previously undescribed interface between Tregs and Th17 cells. The second project focuses on the transcription factor associated with Th17 development, ROR?t, by analyzing the contributions of chemokines in driving these cells to the gut (an extension of the previous granting period) and the role that IL23 plays in the development of Th17 mediated inflammation (taking advantage of murine models developed by the PI). The third project also reflects the evolution of studies from the first granting period by studying the role of the transcription facto IRF8 (ICSBP) on Th17 differentiation (acting as a negative regulator of IL17 production and ROR?t function) and its role in IBD pathogenesis. The fourth project is new to this PPG but takes advantage of the growth of mucosal immunology at Mount Sinai. Dr. Julie Blander studies the role of TLR signaling in Th17 responses in vitro and in vivo using infected vs. uninfected apoptic cells including an infection model (C. rodentium). Her studies fit perfectly with the other projects in our program and her participation in the group provides her access to unique resources to study murine and human IBD. At the same time, she provides models (C. rodentium) that will be helpful for the other PPG members. Overall the focus and interactive nature of the program (20 joint publications in 4 years, 3 additional NIH grants on related areas) provide a solid basis for a productive outcome.

Public Health Relevance

The studies detailed in this proposal focus new light on a pathway involved in mediating mucosal inflammation. It has direct relevance to IBD pathogenesis and may add new insights leading to novel therapies. TABLE OF CONTENTS Overall Description 2

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK072201-09
Application #
8730606
Study Section
Special Emphasis Panel (ZDK1-GRB-8 (O1))
Program Officer
Hamilton, Frank A
Project Start
2005-07-01
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
9
Fiscal Year
2014
Total Cost
$1,762,464
Indirect Cost
$721,928
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Blander, J Magarian (2016) The comings and goings of MHC class I molecules herald a new dawn in cross-presentation. Immunol Rev 272:65-79
Blander, J Magarian (2016) Death in the intestinal epithelium-basic biology and implications for inflammatory bowel disease. FEBS J 283:2720-30
Campisi, Laura; Barbet, Gaetan; Ding, Yi et al. (2016) Apoptosis in response to microbial infection induces autoreactive TH17 cells. Nat Immunol 17:1084-92
Parkunan, Salai Madhumathi; Randall, C Blake; Astley, Roger A et al. (2016) CXCL1, but not IL-6, significantly impacts intraocular inflammation during infection. J Leukoc Biol 100:1125-1134
Legarda, Diana; Justus, Scott J; Ang, Rosalind L et al. (2016) CYLD Proteolysis Protects Macrophages from TNF-Mediated Auto-necroptosis Induced by LPS and Licensed by Type I IFN. Cell Rep 15:2449-61
Ting, Adrian T; Bertrand, Mathieu J M (2016) More to Life than NF-κB in TNFR1 Signaling. Trends Immunol 37:535-45
Roulis, M; Bongers, G; Armaka, M et al. (2016) Host and microbiota interactions are critical for development of murine Crohn's-like ileitis. Mucosal Immunol 9:787-97
Wang, Juan; Peng, Liang; Zhang, Ruihua et al. (2016) 5-Fluorouracil targets thymidylate synthase in the selective suppression of TH17 cell differentiation. Oncotarget 7:19312-26
Dong, Xiaonan; Cheng, Adam; Zou, Zhongju et al. (2016) Endolysosomal trafficking of viral G protein-coupled receptor functions in innate immunity and control of viral oncogenesis. Proc Natl Acad Sci U S A 113:2994-9
Disteldorf, Erik M; Krebs, Christian F; Paust, Hans-Joachim et al. (2015) CXCL5 drives neutrophil recruitment in TH17-mediated GN. J Am Soc Nephrol 26:55-66

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