Blanc SVSE 1 - Sciences de la vie, de la santé et des écosystèmes : Physiologie, métabolisme, physiopathologie, santé publique

-Genetic Diversity and Phenotypic Monotony in non-atherothrombotic arterial pathologies - 2 – GDPM-2

Submission summary

The etiologic diversity of TAAD, our ability to have access to human clinical cohorts and DNA collections, to diseased as well as normal human aortic tissues, and to obtain primary cultures of aortic cells, provide us with a unique opportunity to progress further in the pathology of these frequent and highly morbid cardiovascular diseases.
The aim of our project is to link functional genomics to pathophysiology of aneurysms and dissections of the human thoracic ascending aorta (TAAD) whatever their aetiology, genetic and non-genetic, through final common pathways involving common risk factors of dissection, epigenetic model of SMC expression regulation, SMC disappearance and involvement of tissue proteolysis. As compared to current studies, mainly focused on monogenic forms(13)and on a possible direct relationship between gene mutations and TAAD phenotype, the originality and novelty of our project is its translational genomic approach from highly morbid pathologies to molecular effectors, possible targets for potential new diagnostic and therapeutic tools.

For this purpose we have a number of resources, methods, and know-how at our disposal, including clinical, genetic and tissue/cell databases, experimental models in rat and mice, as well as biological and computational expertise in the analysis of next-generation sequencing and other high-throughput data that will be essential to adapt genomics-scale approaches to the study of vascular pathobiology.

Advances expected from this project are to further delineate
1) the relationship between genetic defects and clinical spectrum in humans, of both mutations in newly recognised genes obtained from large TAA families or within known genes in relation to gene modulators.
2) the biological alterations observed in the human TAA from diverse aetiologies including epigenetic alteration observed in the smooth muscle cells. This may transfer into therapeutic target (cf. losartan studies in progress in patients with Marfan syndrome, derived from the TGFB hypothesis generated in mouse).
3) the pathway linking different genetic defects to a similar phenotype (aortic aneurysm) using both human aortic wall coming from TAA from diverse aetiologies and animal models (now is available a mouse model KI for FBN1, i.e. secondary to an anomaly of the extracellular matrix; we propose to create a mouse model KI for MYH11, i.e. secondary to an anomaly in a contractile protein).
4) animal models of aortic dissection

Project coordinator

Monsieur Guillaume Jondeau (INSERM ADR PARIS VII) – guillaume.jondeau@aphp.fr

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

AMU UNIVERSITE D'AIX MARSEILLE
INSERM UMR970_3 INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - ADR LANGUEDOC-ROUSSILLON - ADR 8
INSERM U781 INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - DELEGATION DE PARIS V
INSERM UMR698 INSERM ADR PARIS VII

Help of the ANR 751,450 euros
Beginning and duration of the scientific project: - 48 Months

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