The interplay between microbial and genetic susceptibility factors is central to the development of inflammatory bowel disease (IBD). Innate mechanisms, in particular through pattern recognition receptor (PRR) pathways, are the initiating drivers of host responses to microbes. Of the 163 loci associated to IBD, a broad range of likely genes modulate host responses to PRR at many levels, and confer some of the largest genetic effect sizes observed in autoimmunity. Despite the significant discoveries in IBD-associated polymorphisms over the past few years, the functional consequences of the vast majority of these loci have yet to be identified. A central outcome of PRR activation by bacterial and viral products is induction of cytokine secretion. To a large extent, IBD is characterized by dysregulated cytokines, and modulation of cytokines plays a primary role in IBD treatment. Inter-individual variation in PRR- induced cytokine secretion influences the balance between susceptibility to infection and inflammatory diseases. We hypothesize that polymorphisms in multiple IBD-associated genes contribute to inter-individual variation in PRR-induced cytokine secretion. Systematic, well- powered studies comprehensively defining the functional alterations driven by disease- associated human variation will provide enormous insight into central mechanisms of IBD;leveraging naturally occurring human genetic variation to systematic """"""""perturb"""""""" an experimental system represents a highly innovative approach for precisely defining established and novel PRR-mediated mechanisms of cytokine secretion. Therefore, we will utilize a large, well- powered cohort to screen for IBD-associated polymorphisms contributing to the variation in PRR-initiated cytokine secretion across individuals, and then define the molecular mechanisms wherein the implicated IBD-associated genes, as well as the identified polymorphisms, regulate PRR-induced cytokine secretion.

Public Health Relevance

We have developed a large functional screen to dissect the contributions of inflammatory bowel disease (IBD)-associated polymorphisms to the variation between individuals in pattern recognition receptor (PRR)-induced cytokine secretion;this provides a uniquely powerful means of determining the functional consequences of a number of IBD-associated loci. We will utilize this screen to first identify those IBD-associated polymorphisms contributing to PRR-initiated cytokines, and then dissect the mechanisms wherein both the genes and the specific polymorphisms within the genes modulate PRR-initiated cytokine secretion. Given the primary role that modulation of cytokine expression has played thus far in the treatment of IBD, we anticipate that studies focused on disease-associated polymorphisms that modulate cytokine secretion will ultimately result in the improved targeting and prioritization of new therapeutic targets for IBD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK099097-01
Application #
8557263
Study Section
Special Emphasis Panel (ZDK1-GRB-2 (M4))
Program Officer
Karp, Robert W
Project Start
2013-09-18
Project End
2018-05-31
Budget Start
2013-09-18
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$362,138
Indirect Cost
$144,638
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Hedl, Matija; Yan, Jie; Abraham, Clara (2016) IRF5 and IRF5 Disease-Risk Variants Increase Glycolysis and Human M1 Macrophage Polarization by Regulating Proximal Signaling and Akt2 Activation. Cell Rep 16:2442-55
Chuang, Ling-Shiang; Villaverde, Nicole; Hui, Ken Y et al. (2016) A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF. Gastroenterology 151:710-723.e2
Abraham, Clara; Dulai, Parambir S; Vermeire, Séverine et al. (2016) Lessons Learned From Trials Targeting Cytokine Pathways in Patients With Inflammatory Bowel Diseases. Gastroenterology :
Hedl, Matija; Proctor, Deborah D; Abraham, Clara (2016) JAK2 Disease-Risk Variants Are Gain of Function and JAK Signaling Threshold Determines Innate Receptor-Induced Proinflammatory Cytokine Secretion in Macrophages. J Immunol 197:3695-3704
Lahiri, Amit; Hedl, Matija; Abraham, Clara (2015) MTMR3 risk allele enhances innate receptor-induced signaling and cytokines by decreasing autophagy and increasing caspase-1 activation. Proc Natl Acad Sci U S A 112:10461-6
Hedl, Matija; Abraham, Clara (2015) A TPL2 (MAP3K8) disease-risk polymorphism increases TPL2 expression thereby leading to increased pattern recognition receptor-initiated caspase-1 and caspase-8 activation, signalling and cytokine secretion. Gut :
Wu, Xingxin; Lahiri, Amit; Sarin, Ritu et al. (2015) T cell-extrinsic CD18 attenuates antigen-dependent CD4+ T cell activation in vivo. J Immunol 194:4122-9
Zheng, Shasha; Hedl, Matija; Abraham, Clara (2015) TAM receptor-dependent regulation of SOCS3 and MAPKs contributes to proinflammatory cytokine downregulation following chronic NOD2 stimulation of human macrophages. J Immunol 194:1928-37
Zheng, Shasha; Hedl, Matija; Abraham, Clara (2015) Twist1 and Twist2 Contribute to Cytokine Downregulation following Chronic NOD2 Stimulation of Human Macrophages through the Coordinated Regulation of Transcriptional Repressors and Activators. J Immunol 195:217-26
Wu, Xingxin; Lahiri, Amit; Haines 3rd, G Kenneth et al. (2014) NOD2 regulates CXCR3-dependent CD8+ T cell accumulation in intestinal tissues with acute injury. J Immunol 192:3409-18

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