Implication of polyunsaturated fatty acid and Transient receptor potential in visceral pain – LIPIDOPAIN
Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders. IBS is characterized by visceral hypersensitivity, associated with altered bowel functions. The lack of knowledge of the disease and of tools for diagnostic and therapeutic represents an important challenge to improve the quality of life of IBS patients. By a bedside to bench study, we have demonstrated that proteases secreted by colonic biopsy of IBS patients were able to induce visceral hypersensitivity. We demonstrated that protease-induced hypersensitivity was linked to activation of the Protease-Activated Receptor-2 (PAR2). The study of the mechanism linked to PAR2-activating protease induce visceral hypersensitivity bring us to focus our interest on the regulation of a member of the TRP (Transient Receptor Potential) superfamily: TRPV4 (Transient Receptor Potential Vanilloid). We demonstrate that TRPV4 mediates visceral hypersensitivity of several mediators implicated in IBS such as histamine, serotonin and PAR2 activation. Importantly, our results suggest that TRPV4 per se or mediators involved in its regulation could constitute new potential therapeutic options for the treatment of abdominal pain, particularly in patients with IBS. TRPV4 is not the only receptor channel in the TRP family which can be implicated in visceral nociception. In fact, a study showed that visceral mechanical hypersensitivity was also mediated by TRPA1 activation. Five TRPs (TRPV1, TRPV3, TRPV4, TRPA1 and TRPM8) which can be regulated by polyunsaturated fatty acid (PUFA) metabolites are expressed on sensory neurons. In IBS patients, plasmatic concentration of some PUFA is increased. Therefore implication of one of these five TRPs in IBS-related pain symptoms is possible and need to be determined. A receptor can only be considered as implicated in pathology if its agonists are present and able to activate the receptor. The presence and functionality of agonists of these five TRPs in pathological tissues have never been reported.
The general objective of the present program is to better understand the lipid-TRP pathway inducing pain symptoms in the context of IBS. We will examine the pathological implication of TRPV4. In a second time, the release of PUFA metabolites in physiological and pathophysiological condition will be quantified. We will study the pharmacological properties on TRPV1, TRPV3, TRPV4, TRPA1 and TRPM8 of PUFA metabolites.
The pathological implication of TRPV4 will be assessed first in human biopsy by quantitative and qualitative study of TRPV4 expression. In mice deficient for TRPV4, we will determine if TRPV4 could be a new therapeutic target in IBS-related pain. PUFA metabolites will be quantified by mass spectrometry in biopsies of IBS patients. The quantification of these metabolites will proprose as biomarkers of the disease. The characterisation of the pharmacological properties of PUFA metabolites will demonstrate which TRPs channels could be implicated in the regulation of visceral hypersensitivity.
By this project we expect to demonstrate the therapeutic potential of TRP channels and PUFA metabolites in IBS-related pain. Furthermore, we hope to increase the knowledge in the management of visceral pain and to use the quantification of PUFA metabolites as diagnostic.
Project coordination
Nicolas CENAC (Institut national de la santé et de la recherche médicale ) – nicolas.cenac@inserm.fr
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Partner
INSERM UMR 1043 Institut national de la santé et de la recherche médicale
Help of the ANR 315,070 euros
Beginning and duration of the scientific project:
September 2012
- 36 Months