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.
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.
|Luong, Phi; Hedl, Matija; Yan, Jie et al. (2018) INAVA-ARNO complexes bridge mucosal barrier function with inflammatory signaling. Elife 7:|
|Schumacher, Michael A; Hedl, Matija; Abraham, Clara et al. (2017) ErbB4 signaling stimulates pro-inflammatory macrophage apoptosis and limits colonic inflammation. Cell Death Dis 8:e2622|
|Bist, Pradeep; Cheong, Wan Shoo; Ng, Aylwin et al. (2017) E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP. Nat Commun 8:15865|
|Yan, Jie; Hedl, Matija; Abraham, Clara (2017) An inflammatory bowel disease-risk variant in INAVA decreases pattern recognition receptor-induced outcomes. J Clin Invest 127:2192-2205|
|Lahiri, Amit; Hedl, Matija; Yan, Jie et al. (2017) Human LACC1 increases innate receptor-induced responses and a LACC1 disease-risk variant modulates these outcomes. Nat Commun 8:15614|
|Zhu, Shu; Ding, Siyuan; Wang, Penghua et al. (2017) Nlrp9b inflammasome restricts rotavirus infection in intestinal epithelial cells. Nature 546:667-670|
|Abraham, Clara; Dulai, Parambir S; Vermeire, Séverine et al. (2017) Lessons Learned From Trials Targeting Cytokine Pathways in Patients With Inflammatory Bowel Diseases. Gastroenterology 152:374-388.e4|
|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|
|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|
|Hedl, Matija; Abraham, Clara (2016) 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 65:1799-1811|
Showing the most recent 10 out of 21 publications