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Molecular Mechanism Of Endocardial Mechanotransduction

Reference : PhD Julien VERMOT

Offer publication : April 6, 2016

In humans, cardiac valve defects account for 20-30% of all congenital cardiovascular malformations, with an incidence of ≈2% in all live births. The origins of the defects are multifactorial but are usually associated with genes important for heart valve development, such as signaling factors (Notch1, TGFβ), and Filamin A (FLNA), an actin interacting protein.
The forces generated in the heart are significantly higher than in the vascular system. Consequently, the unknown molecular mechanisms underlying EdC flow sensitivity are likely to be unique. We will identify mechanosensitive channels acting in EdCs and to identify their downstream mechanotransduction pathways and rescuing heart valve development when mechanical forces are low.

The first part of the project will be to identify mechanosensitive channels specifically expressed in EdCs during embryonic heart development. To search for mechanosensitive channels specifically expressed in EdCs in vivo, the phD will perform a large-scale in situ hybridization screen on ZF
embryos at key stages of heart valve formation and in adults. Selected genes with specific EdC expression will be subjected to genetic (gain- and loss-of-function) analyses, in search of phenotypic defects associated with formation of the heart valve. In addition, gene expression analysis will be performed on FACS-isolated GFP+ EdCs. These approaches will enable us to ascribe a phenotype and mechanosensitivity-potential to the selected receptors within the endocardium. The subcellular localisation of the identified channels will be determined by imaging fluorescently labeled fusion proteins15 after gene knockin suitable for Correlative Light Electron Microscopy (CLEM), which offers nanometric resolution.

The second part will be to demonstrate the mechanosensitivity of the identified channels in vivo. Once the mechanosensitive channels have been identified, the phD student will demonstrate their sensitivity to mechanical stimuli using experimental approaches to generate a mechanical stimulus directly on the EdCs in vivo, mimicking the cellular forces generated in the heart. By measuring calcium influx in response to each mechanical stimulus, experimental approaches will also be used to measure the force necessary to induce intracellular signalling.

- WISHED SKILLS : Molecular and cell biology


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Application Deadline : Dec. 31, 2016

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