Inflammatory bowel disease (IBD) is a significant risk factor in the development of colorectal cancer (CRC), a leading contributor to cancer-related deaths in the United States. Both IBD and CRC are commonly associated with the exaggerated production of inflammatory cytokines which are regulated by the activation of various cell signaling pathways including the NF-kB family of transcription factors, IL-1, COX2 and IL6. The NLR (nucleotide binding domain and leucine-rich-repeat-containing or NOD-like receptor) family of proteins has received much attention in IBD research due to their role in regulating inflammation and the genetic association of certain NLR proteins with Crohns'disease. NLR is a multi-member gene family that encodes a group of cytosolic proteins that are involved in the intracellular sensing of microbial products as well as damage-associated molecular patterns. Thus NLR family members are crucial regulators of innate immune response which is an important link to IBD and CRC. We and others have begun to show the association of the inflammasome-associated NLRs in models of experimental colitis (EC) and colitis-associated colon cancer (CAC). This group of proteins respond to pathogen derived products and can assemble into inflammasomes in conjunction with the key NLR adaptor protein, ASC (apoptotic speck containing protein with a CARD) to activate the IL-1B-processing enzyme caspase-1. Caspase-1 activation then leads to the cleavage and maturation of pro- IL-1B and IL-18. In addition to the analyses of these well- studied inflammasome components in models of EC and CAC, we have data to indicate a strong role for other NLRs which have anti-inflammatory functions, and can attenuate the clinical outcome in these models. This proposal plans to examine the roles of ASC and these other NLRs in these disease models. We will further delineate the molecular mechanisms by which these proteins affect disease outcome.

Public Health Relevance

Innate immune sensors or receptors are crucial for immune response during inflammatory disorders and during microbial infections. We have been studying a new family of immune sensors called NLRs, and have found that several of these play crucial roles in the control of colitis and inflammation-induced colon cancer. This proposal will explore the mechanism by which these NLRs regulate gastro-intestinal inflammation and tumorgenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA156330-04
Application #
8641091
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Howcroft, Thomas K
Project Start
2011-05-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
4
Fiscal Year
2014
Total Cost
$319,871
Indirect Cost
$103,742
Name
University of North Carolina Chapel Hill
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Rodgers, Mary A; Bowman, James W; Fujita, Hiroaki et al. (2014) The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation. J Exp Med 211:1333-47
Robbins, Gregory R; Wen, Haitao; Ting, Jenny P-Y (2014) Inflammasomes and metabolic disorders: old genes in modern diseases. Mol Cell 54:297-308
Zhang, Lu; Mo, Jinyao; Swanson, Karen V et al. (2014) NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING. Immunity 40:329-41
Guo, Haitao; Gao, Jianmei; Taxman, Debra J et al. (2014) HIV-1 infection induces interleukin-1? production via TLR8 protein-dependent and NLRP3 inflammasome mechanisms in human monocytes. J Biol Chem 289:21716-26
Wen, Haitao; Miao, Edward A; Ting, Jenny P-Y (2013) Mechanisms of NOD-like receptor-associated inflammasome activation. Immunity 39:432-41
Lei, Yu; Wen, Haitao; Ting, Jenny P Y (2013) The NLR protein, NLRX1, and its partner, TUFM, reduce type I interferon, and enhance autophagy. Autophagy 9:432-3
Wen, Haitao; Ting, Jenny P-Y; O'Neill, Luke A J (2012) A role for the NLRP3 inflammasome in metabolic diseases--did Warburg miss inflammation? Nat Immunol 13:352-7
Allen, Irving C; Wilson, Justin E; Schneider, Monika et al. (2012) NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF-?B signaling. Immunity 36:742-54
Allen, Irving C; Moore, Chris B; Schneider, Monika et al. (2011) NLRX1 protein attenuates inflammatory responses to infection by interfering with the RIG-I-MAVS and TRAF6-NF-?B signaling pathways. Immunity 34:854-65
Wen, Haitao; Gris, Denis; Lei, Yu et al. (2011) Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol 12:408-15

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