PHACTR1 : a new marker

PHACTR1 : a new marker of early vessel ageing (WP2) : S. Debette, I. Sibon, C. Tzourio, A Bikfalvi, E Roux, T Couffinhal, C James (Inserm U897; Inserm U1029; Inserm U1034 - Department of Cardiovascular diseases - Department of Neurology and Stroke Unit - Laboratory of Hemostasis)

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The PHACTR1 gene

Recently, hypothesis-free genome-wide association studies (GWAS) have revealed robust associations of common genetic polymorphisms in the PHACTR1 gene (encoding Phosphatase and Actin Regulator 1) with a range of frequent vascular diseases, including myocardial infarction, coronary calcifications, cervical artery dissection (a major cause of ischemic stroke in young adults), as well as migraine. (Anttila et al., 2013; Coronary_Artery_Disease_(C4D)_ Genetics_Consortium., 2011; Debette et al., 2015; Deloukas et al., 2013; Freilinger et al., 2012; Hager et al., 2012; Kathiresan et al., 2009; Lu et al., 2012; Mehta, 2011; O'Donnell et al., 2011; Schunkert et al., 2011) PHACTR1 is located in a highly conserved genomic region, suggesting a crucial involvement in biological processes,(Allen et al., 2004) but its function is poorly understood. Experimental studies revealed a pivotal role in vascular tube formation and actin polymerization, suggesting a possible role in angiogenic processes and endothelial functioning.(Allain et al., 2012; Jarray et al., 2011) Upregulation of PHACTR1 by TGFβ has been described in breast cancer cell lines,(Fils-Aime et al., 2013) potentially pointing to a connection with the TGFβ signaling pathway, which is also implicated in genetic predisposition to migraine,(Anttila et al., 2013) and plays a key role in Marfan and Loeys-Dietz syndromes, two inherited connective tissue disorders causing aortic dissection.(Goumans et al., 2009; Loeys et al., 2005)

The role of PHACTR1 and vascular functions

Understanding the mechanisms by which PHACTR1 appears to influence key vascular functions could have major applications for the treatment of two severe and disabling vascular conditions, myocardial infarction and cervical artery dissection.
In this workpackage we aim at taking a unique multidisciplinary approach at exploring the role of PHACTR1 on vascular function and disease. We will first expand our investigations of genetic variants in PHACTR1 in relation with cervical artery dissection, using next generation sequencing and transcriptomic approaches. Second, we will examine PHACTR1 signaling and its role in endothelial and pericyte properties and angiogenic response. Third, we will establish transgenic loss of function (LOF) mice strains (including endothelial cell specific LOF), using novel Crispr / Cas9 technology allowing fast genome editing, and explore the 3D vascular architecture of transgenic mice. Fourth, we will examine the effect of PHACTR1 endothelial cell specific LOF on post-ischemic myocardial repair, and thrombosis formation.

  • Genetic variation in PHACTR1 and susceptibility to cervical artery dissection
  • PHACTR1 signaling and role in endothelial and pericyte properties and angiogenic response
  • Construction of transgenic lines LOF with new techniques Crispr / Cas9
  • Effect of PHACTR1 endothelial cell specific LOF on 3D vascular architecture and vessel stenosis - micro-scan approach
  • Effect of PHACTR1 endothelial cell specific LOF on post-ischemic myocardial repair
  • Effect of PHACTR1 endothelial cell specific LOF on tumoral angiogenesis 

  • Effect of PHACTR1 endothelial cell and blood cell specific LOF on 
thrombosis 


Updated on 09/06/2016