Intracranial aneurysm (IA) is an asymptomatic cerebrovascular abnormality affecting 3.2% of the general population. The devastating complication of IA is its rupture, resulting in subarachnoid haemorrhage that can lead to severe disability and death. Unfortunately, there are neither reliable clues nor diagnostic tools to predict the formation and/or the fate of an IA in a given individual. Also, there is no pharmacological drug available to prevent the rupture of aneurysm and subsequent subarachnoid haemorrhage. Current treatments are invasive with a significant risk of procedural morbidity. Thus, still now, the management of patients with IA remains extremely challenging and still controversial.
Although the pathogenesis of IA has been the subject of many studies for the last decade, the mechanisms underlying IA formation, growth and rupture are still mostly unknown and relevant animal models of IA are not available. Familial history of IA predisposes to IA formation and rupture and increasing evidence suggest a genetic component of IA formation, with heterogeneous modes of inheritance and penetrance.
Our project, gathering neuroradiologists, geneticists and vascular biologists, addresses the urgent need to understand the pathogenic mechanisms of IA to develop diagnostic and predictive tools of risk of IA. We propose to identify IA-causing variants by whole-exome sequencing in familial forms of the disease. We hypothesise that the functional analysis of the causal/susceptibility variants thus identified will provide clues to understanding the pathological mechanisms of IA formation, and the bases for developing diagnostic tools. Our project aims at meeting this challenge. Based on our preliminary data that already allowed to identify such a variant, and the combination of genetic and functional investigations, the specific objectives of our project are:
- To identify IA-causing variants in familial forms of the disease by whole-exome sequencing;
- To understand the function of these genes/variants in the formation and rupture of IA by molecular and cellular approaches and generation of relevant animal models;
- To discover potential biomarkers of risk of IA formation and/or rupture.
Madame Gervaise LOIRAND (UMR Inserm 1087-Cnrs 6291 Unité de Recherche de l'Institut du thorax)
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.
CHU Nantes CHU Nantes - Neuroradiologie diagnostique et interventionnelle
UMR Inserm 1087-Cnrs 6291 UMR Inserm 1087-Cnrs 6291 Unité de Recherche de l'Institut du thorax
UMR Inserm 1161 UMR-S Inserm 1161
IPNP Institut de Psychiatrie et Neurosciences de Paris
Help of the ANR 405,886 euros
Beginning and duration of the scientific project: September 2015 - 36 Months