PAPIS

Chronic constipation constitutes an extremely frequent symptom of consultation in the pediatric discipline. A study undertaken by French High Official Health organization in 2005 evaluates between 300 to 600,000 the number of children (from 0.5 to 8 years old) suffering each year from constipation and estimates that half of the children will require one medicamentous assumption. Complication could conduct to surgery or in more severe condition multivisceral transplantation. In adults, up to 20% of the population can be affected by GastroIntestestinal (GI) motility disorders during their life. Moreover, constipation, incontinence and diarrhea are frequently encountered in patients suffering from chronic diseases and in the ageing population. Undiagnosed or unsatisfactorily treated disorders have serious familial and societal effects. Studying the development/immaturity and the physiological dedifferentiation (plasticity) of the GI smooth muscle, our team demonstrated that RNA-binding protein essential for immaturity of GI smooth muscle cells (SMC) is involved in the SMC plasticity process. We also found that this RNA-binding protein was abnormally expressed in patients of digestive myopathies, suggesting that the immaturity of SMC leads to the observed functional impairment. In this context, we demonstrated that aberrant SMC dedifferentiation process is present in pediatric and adult patients suffering from Chronic Intestinal PseudoObstruction (CIPO), bringing for the first time a positive diagnosis that identified and characterized immature SMCs associated with CIPO syndrome. Our objectives are to study the structure-function relationship of RNA-binding protein and its downstream pathways during the remodeling of digestive smooth muscles in digestive motility disorders in order to develop specific stapled peptides and foldamers that target protein-protein interaction domains essential for its function. Our consortium involves 3 complementary partners with well-recognized expertises on Gastroenterology, Structural Biology and Protein-Protein Interaction (PPI) inhibitor. Our project will focus on CIPO syndrome, a severe and rare GI motility disorder characterized by recurring and chronic episodes of obstruction without any mechanical cause. Our expertise and complementary approaches will allow us to develop innovative peptide mimetics to inhibit SMC dedifferentiation process and to improve pediatric and adult CIPO SMC function. CIPO syndrome also is recurrent in patients. In line with this feature, SMC plasticity takes place in different chronic diseases such as inflammatory, diabetic or metabolic diseases. Our research on rare disease will help us to understanding more common and chronic diseases and our original PPI inhibitors could be tested to improve their GI dysfunction. This innovative study, involving 3 complementary partners, should lead to a better understanding of the mechanisms controlling the physiopathology of digestive muscle cells and the development of new innovative peptide therapeutic strategies.