Colorectal cancer is a serious medical complication for individuals suffering from ulcerative colitis and other inflammatory bowel diseases (IBDs). Signaling cascades which alter inflammatory activation are of specific relevance to the development of Colitis-associated Colorectal Cancer (CAC), as dysregulation of inflammation has been found to be associated with many types of cancers and inflammatory diseases. Our lab and others have recently characterized the NLR (NBD-LRR) family of proteins, which have been proven to be essential mediators of innate immune responses to microbes and environmental stressors. One subset of NLR family members have been shown to form multiprotein complexes, defined as inflammasomes, which can be further characterized by the specific NLR involved in formation. NLR inflammasomes function, in a cell type and stimuli specific manner, to process IL-12 and IL- 18 into mature cytokines. These proinflammatory cytokines have been implicated in IBDs and cancer. In addition to the inflammasome forming NLRs, a second sub-group of NLRs have been shown to function as negative regulators of inflammation through the modulation of NF-:B signaling. Dysregulation of NF-:B signaling is a critical component in the pathogenesis of inflammation and tumorigenesis in the gut. OBJECTIVES: Our working hypothesis proposes that the inflammasome associated NLR, NLRP3, and the anti-inflammatory NLR, NLRP12, both function to protect the host from ulcerative colitis and colitis associated cancer through the modulation of NF-:B signaling in innate immune cells. However, the NLRP1 inflammasome functions in either stromal or cancer cells to mediate inflammation and tumorigenesis through a mechanism that is independent of the NLRP3 protein.
SPECIFIC AIM 1 : Examine the contribution of the inflammasome components Pycard, Caspase-1 and NLRP1 in the development of EC and CAC.
SPECIFIC AIM 2 : Refine the mechanisms by which NLRP3 mediates its physiological effects on EC and CAC.
SPECIFIC AIM 3 : Evaluate the ability of NLRP12 to function as a negative regulator of tumorigenesis during CAC through its ability to suppress non-canonical NF-:B signaling. STUDY DESIGN: We will utilize genetically manipulated mice lacking specific NLRs or inflammasome components to evaluate function in models of inflammatory bowel disease and cancer.
Aim 1 will test the hypothesis that the attenuation mediated by Pycard and Caspase-1 during EC and CAC cannot be attributed to NLRP3, which suggests another NLR inflammasome. Here, we will test the components of the NLRP1 inflammasome as a potential candidate.
Aim 2 will test the hypothesis that NLRP3 attenuation during EC and CAC is associated with the suppression of IL-12 and IL-18 through the modulation, either direct or indirect, of canonical NF-:B activity.
Aim 3 will test the hypothesis that NLRP12 functions as a negative regulator of non-canonical NF-:B signaling to attenuate inflammation and protect the host during EC and CAC.

Public Health Relevance

Inflammation may be a causative agent in tumor development by acting as a tumor promoter. Understanding the role of specific host immune system mediators on the development of colitis- associated colon cancer will be instrumental for the generation of new strategies targeting the prevention and/or treatment of this disease. Identifying the specific cell types and the relevant NLRs that are involved in regulating the ensuing inflammatory response following the induction of gastrointestinal inflammation and subsequent tumorigenesis would be of immense scientific and clinical value.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Scientist Development Award - Research & Training (K01)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Podskalny, Judith M,
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Virginia Polytechnic Institute and State University
Schools of Veterinary Medicine
United States
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Rothschild, Daniel E; McDaniel, Dylan K; Ringel-Scaia, Veronica M et al. (2018) Modulating inflammation through the negative regulation of NF-?B signaling. J Leukoc Biol :
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Williams, Tere M; Leeth, Rachel A; Rothschild, Daniel E et al. (2015) The NLRP1 inflammasome attenuates colitis and colitis-associated tumorigenesis. J Immunol 194:3369-80
Allen, Irving Coy (2014) Non-Inflammasome Forming NLRs in Inflammation and Tumorigenesis. Front Immunol 5:169

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