Projet 2

Thesis project

Na+/H+ Exchangers (NHEs) are expressed in all biological systems. In vertebrates, three isoforms of NHEs are mostly restricted to intracellular compartments. Their sequences are highly conserved and their mRNAs are detected in a number of organs in mammals, including the central nervous system. In 2006, a deletion of the gene encoding NHE-7 was found in mental retardation patients (5-6) and in 2008 two studies have linked defects NHE-6 and NHE-9 to genetic syndromes associating cognitive disorders autism or attention deficit type, epilepsy and cerebellar degeneration (7). Despite this importance, little is known about the role of these intracellular exchangers in the regulation of the pH of intracellular compartments. Indeed, the study of their biochemical and pharmacological characteristics, essential to understanding their function, has encountered the fact that they are sequestered within the cells and are very poorly accessible for measurements. We managed to solve this problem by selecting cell lines capable of withstanding acute cytosolic acidification, through expression NHE-6 or 7 at the plasma membrane. We now use an arsenal of ion transport measurement techniques developed in our team (8-9) to study the kinetics, ion selectivity, pharmacology and regulation of these carriers in a quasi-exhaustive manner. In parallel we are studying their localization in organs and particularly in the brain. We work with clinical groups whose goal is to identify mutations in patients with mental disorders like autism, mental retardation, or attention deficit. The PhD student will use the tools available in our laboratory (somatic genetics, fast kinetics, video microscopy and imaging etc) to study the NHE6 and NHE9 exchangers for all that concerns their ion selectivity, regulation, pharmacological profile, interactome and their cerebral and intracellular localization. The gained information will be used to measure their impact on vesicular pH, on trafficking and ultimately to understand their brain function and role in neurodevelopment. The PhD student will also be involved in the genotyping of cohorts of patients and study of the impact of the mutations that will be eventually be found. This will bring together their function and patient phenotypes.

 

CNRS-UMR 7370 -Laboratoire de Physiomedecine moléculaire, Université de Nice-Sophia antipolis Faculté de Médecine, 28 Av Valombrose, Tour Pasteur

06108 Nice, France.   e-mail to Laurent Counillon