Unité mixte de recherche INSERM-Paris7 U1161 – Genetics and physiopathology of cerebrovascular diseases
Elisabeth TOURNIER LASSERVE
Faculté de Médecine Paris Diderot Paris 7 - site Villemin
10 avenue de Verdun - 75010 Paris
Téléphone : +33 (0)1 57 27 85 93
Télécopie : +33 (0)1 57 27 85 94
- Team1 (Leader: Joutel Anne)
Pathogenesis of cerebral small vessel diseases .
- Team 2 (Leader: Tournier-Lasserve Elisabeth)
Hereditary cerebrovascular diseases gene identification and investigation of the mechanisms of cerebrovascular dysplasia.
- Team 3 (Leader: Chabriat Hugues)
Biomarkers of small vessel disease.
- Team 4 (Leader: Debette Stéphanie)
Epidemiology of cerbrovascular diseases.
Cerebrovascular disease (CeVD) is a major public health issue; its major complication is ischemic or hemorrhagic stroke that causes disability, cognitive impairment and death. CeVD is an extremely heterogeneous condition not only in its clinical presentation but also in its pathophysiological mechanisms, prognosis and treatment strategies.
U1161 is a highly interactive research laboratory focusing on several well-defined subtypes of CeVD, from genes and mechanisms to clinical and therapeutic applications. It is part of the recently created DHU NeuroVasc Paris-Sorbonne, which also includes also the Department of Neurology, the National Reference Genetics laboratory for Neurovascular disorders (NRGN) and the clinical National Referral Centre for Rare CeVD (CERVCO; www.cervco.fr) at the Lariboisière-Fernand Widal hospital in Paris, which are headed by 2 senior members of U1161. Previously, members of this laboratory have produced some of the seminal work on CADASIL, the most frequent hereditary small vessel-disease of the brain and hereditary Cerebral Cavernous Malformations (CCM).
Particularly, during the past 5 years, members of this laboratory have generated unique mouse models recapitulating the main features of CADASIL and CCM. They have provided compelling evidence for cerebrovascular dysfunction and microcirculatory failure as the earliest consequences of pathogenic Notch3 mutations in CADASIL. They demonstrated that the development of CCM lesions is strongly restricted to the venous bed and tightly correlated with intense angiogenesis developmental stages. Finally, this lab has characterized both at the clinical and molecular level, two novel monogenic forms of small-vessel-disease of the brain and two novel inherited syndromic Moyamoya.
For the next five years, members of this laboratory will combine their expertise to pursue four main goals:
- To get a better understanding of the pathogenesis of CADASIL and CCM. Exploiting our unique cohort of 320 patients with CADASIL, we will assess the neurovascular coupling and the clinical significance of morphological changes of the brain cortex. Using our newly created CADASIL and CCM mouse models, we will pursue the identification of the molecular mechanisms by which Notch3 toxic gain-of-function drives small vessel pathology and, will elucidate the signaling pathways underlying the spatially and temporally restricted CCM competence of venous endothelial cells.
- To apply the knowledge gained from the above studies to develop new therapeutic approaches in CADASIL and CCM. On first, we will assess therapeutic anti-Notch-3 antibodies to the clearance of Notch3 deposits in CADASIL animal model as a proof-of principle for a disease modifying therapy.
- To identify the genes and improve the diagnosis of several well-defined subtypes of CeVD. Taking advantage of very well defined collections of patients with cerebral CeVD gathered in the past 20 years by this laboratory, the NRGN and the CERVCO, we will pursue the identification of the causative mutations in monogenic forms of small-vessel-disease of the brain and syndromic Moyamoya of unknown etiology, by employing high throughput technologies including resequencing of targeted linked regions, whole exome/genome sequencing and whole genome array screening.
- To identify the determinants of common forms of CeVD. We will identify the genetic determinants of common forms of small-vessel-disease (SVD). On first, we will assess the contribution of CADASIL pathway genes using genetic studies in human and functional studies in the mouse. On second, we will expand our existing cohort of patients with SVD to conduct GWAs studies. Also, we will also expand the identification of genetic risk factors of cervical artery dissection.
These projects are supported by national (PHRC, ANR), European (2 Eranet Neuron) and Transatlantic (2 Leducq networks) agencies as well as a pharmaceutical company (Lundbeck S/A).