TRPM4 channel and cellular interactions leading to deleterious aortic valve remodeling

Aortic stenosis (AS) is a pathology due to the deleterious remodeling of the aortic valve

(fibrosis and calcification) whose incidence increases with aging. To avoid valve replacement,

it is essential to identify the cellular and molecular players of this remodeling which would

allow the development of other therapeutic approaches. It is in this area that we are doing

our research at the UR 4650 PSIR by focusing on the TRPM4 ion channel. We have shown its

implication in AS in mice and in the remodeling of human valvular interstitial cells (VIC) which

are key elements of the AS.

The aim of the thesis will be to evaluate the role of the TRPM4 channel in remodeling involving

communication between valvular endothelial cells (VECs) which cover the valve leaflets and

the VICs. It is part of a project funded by the ANR which we are leading and carried out in

collaboration with a partner from Rouen (INSERM U1096 Envi).

The research will use cells isolated from human aortic valves from the Caen or Rouen

University Hospitals, thus ensuring strong translational potential. A first task will evaluate

variations in intracellular calcium in cultured VICs following pharmacological inhibition or

molecular repression of the TRPM4 channel, calcium being a major player in the signaling

pathways leading to remodeling. A second task will describe the effect on the VIC of molecules

produced by the VEC. The activity of the TRPM4 channel and its

possible modulation will be evaluated. Finally, a third task will determine the role of TRPM4

in the remodeling of VICs in the presence of VECs in coculture in order to approach conditions

found in a valve leaflet. Ultimately this project will contribute to deepening our knowledge of

the role of TRPM4 in the development of AS and thus determining whether it would be a

relevant therapeutic target.

Our research group UR4650 PSIR brings together 12 permanent members, including clinicians and fundamentalists. The scientific project focuses on the search for new strategies to better assess and limit cardiovascular remodeling. The first area, within which the thesis topic is integrated, aims to study the role of calcium signaling in this cardiovascular remodeling by combining electrophysiological, pharmacological, and molecular biology approaches. A second area focuses on imaging cardiovascular remodeling.

Our unit participates in the CARNAVAL University Hospital Federation, which brings together teams from the universities and teaching hospitals of Rouen, Amiens, Lille, and Caen, working on the issue of aortic stenosis and heart failure. This FHU provides a solid scientific framework for this thesis project.

The candidate will hold a masters degree (or M2 in progress) in the field of biology and health with solid training in the themes of cell signaling and theoretical knowledge in electrophysiology. From a practical point of view, experience in patch-clamp techniques and cell culture will be appreciated. Practice of basic biochemistry and molecular biology techniques will be appreciated. Speaking in French or English is required.