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Groupe Schild

Laurent Schild, Full Professor, Director of the DPT

phatox-5816.jpg (Département de Pharmacologie & ToxicologieFaculté de...

Laurent Schild received his MD from the University of Lausanne.
From 1979 to 1984, he was resident in Pathology, Internal medicine, Pharmacology. He received a doctorate degree in medicine in 1984. From 1984 to 1990, he joined the Yale University Medical School for a postdoctoral training in the Department of Physiology and the Department of Pharmacology. He returned to Lausanne in 1990 at the Department of Pharmacology and Toxicology where he started an independent research on the biophysics and pharmacology of ion channels. In 1999 he was appointed associate professor and 2006 full professor. Since 2007, he is chairman of the Department of Pharmacology & Toxicology.

 

Research domain

Epithelia form barriers that separate the body fluids from the outside world, and serve to maintain the water and solute composition of the organism. To achieve this essential function, epithelial cells are capable of vectorial transports of solutes and water driven by ion pumps, transporters or channels located at the plasma cell membranes. Among the ion channels found in epithelia, the epithelial sodium channel (ENaC) allows the entry of Na+ ions into the cell. This selective entry of Na+ ions into the cell represent the first and limiting step of a vectorial transcellular transport of sodium in series with the Na+ K+-ATPase. This vectorial transport is particularly important in epithelia such as the kidney or the intestine, that actively absorb Na+ ions and water in order to prevent massive body loss of water and electrolytes.
This epithelial function was essential for adaptation to terrestrial life. The pathological relevance of this phenomenon for potential pharmacologic interventions comes from genetic studies demonstrating the critical role of ENaC in the control of extracellular fluid volume and blood pressure.

Our research focus on the epithelial sodium channel ENaC and aims at a better understanding of the relations existing between the structures the functional of this channel. Three-dimensional structures at the atomic level are available for a homolog of ENaC and can be used as template to understand the structural basis of various aspects of channel function by identifying important functional domains on the channel protein. Of course this research strategy requires as prerequisite strong experimental evidence that the available 3-dimensionsal structure of the protein represent a functional channel.  This research has implications for the design and the development of new drugs targeting ENaC based on rationale structural and functional considerations. This research has translational implications for various inherited monogenic diseases caused by genetic variants encoding ion channels (channelopathies). It contributes to our understanding of the relation existing between the genotype and the phenotype, and allows to correlate the clinical severity of the disease and the degree of channel dysfunction. Ultimately, this knowledge will help to design new therapeutic strategies for the treatment of rare monogenic diseases.

 

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Figure legend: The figure combines a 3-D structure model of a single subunit of the epithelium sodium channel ENaC, a recording of the ENaC openings and closings, and in the background an example of  a kinetics model developed to understand the complexity of the behavior and activity of a channel close to ENaC that belongs to the same ion channel family. This figure illustrates the multidisciplinary approach of our research, from functional, to structural, via biophysical kinetics studies.

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