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Project

Resolvines as potential new therapeutic targets for the treatment of visceral hypersensitivity

About 10-20 % of individuals worldwide suffer from Irritable Bowel Syndrome (IBS), which is one of the most common gastrointestinal diseases in the western world. Characteristic symptoms vary from patient to patient but include chronic discomfort and abdominal pain associated with altered bowel habits in the absence of an organic cause. About 60% of IBS patients suffer from increased abdominal pain perception or visceral hypersensitivity (VHS). The exact mechanism involved in VHS remains unclear but aberrant immune / mast cell activation has been proposed. 
The two most characterized triggers for the development of IBS are psychological stress on the one hand, and an episode of bacterial gastroenteritis on the other hand. Of note, psychological stress is repeatedly shown to trigger mast cell activation with subsequent VHS and increased permeability, two hallmark features of IBS. The mechanisms underlying persistent IBS symptoms in 10-30% of patients who suffered from infectious gastroenteritis however are less well understood. To obtain more insight in the pathogenesis of this subtype of IBS, we recently developed a mouse model. We hypothesized that an infection would not only trigger an immune response to the infectious agent, but also to innocent bystander present at the time of infection (such as ovalbumin in our model). with production of antibodies and subsequent mast cell activation. Of great interest, we showed that re-exposure to OVA (oral gavage) in the post-infectious phase resulted in VHS and increased permeability, but only in mice with a predominant Th2 immunogenetic background (Balb/c). In view of the recent insight that innate lymphoid cells type 2 (ILC2) play a central role in Th2 polarization in parasite infection and asthma, we will especially focus on the possible involvement of these newly discovered players in the development of the bystander immune response and VHS. We anticipate that a Th2 polarizing environment (generated by the host (genetics) or the infectious agent) drives a Th2 immune response with the activation of ILC2 subsequently polarizing dendritic cells leading to a Th2 immune response to bystander antigens with the generation of Th2 cells, B cells, production of IgE or G and ultimately mast cell activation.
In the present thesis, we aim to further unravel the mechanisms underlying the post-infectious VHS and increased permeability observed in our recently developed murine model. We will especially focus on 1. the involvement of mast cells and the underlying mechanism of activation, and 2. the mechanisms underlying Th2 polarization. With respect to the latter, the potential role of ILC2 will be studied, not only in our model, but also in IBS samples.

Date:18 Aug 2014 →  1 Mar 2020
Keywords:visceral, hypersensitivity
Disciplines:Endocrinology and metabolic diseases, Biomarker discovery and evaluation, Drug discovery and development, Medicinal products, Pharmaceutics, Pharmacognosy and phytochemistry, Pharmacology, Pharmacotherapy, Toxicology and toxinology, Other pharmaceutical sciences, Gastro-enterology and hepatology
Project type:PhD project