Individual research ESR 11

Dissecting the role of FOXO transcription factors in venous and lymphatic malformations


Objectives:

  • Study the expression and subcellular localization of FOXOs (FOXO1/3/4) in ECs of defined models of venous and lymphatic anomalies in vitro and in vivo
  • Assess the role of aberrant FOXO signalling in VMs and LMs using single and compound knockout and knockin mice
  • Analyse the cellular consequences and transcriptional signatures of FOXO deficiency in blood and lymphatic endothelial cells in vitro (e.g. CRISPR/CAS9, iPS-EC / iPS-LEC)
  • Study endothelial metabolic adaptations in FOXO-deficient blood and lymphatic endothelial cells and assess their role for sustaining VMs and LMs.
  • Screen for mutations in the human FOXO genes in patients with diagnosed VMs/LMs

Expected Results:

  • Establish ‘FOXO inactivation’ as a mechanism for venous and lymphatic malformations (VMs, LMs);
  • Establish EC-specific FOXO knockout mice as novel mouse models to study the cellular mechanisms of VMs and LMs;
  • Uncover cellular mechanisms driving VMs and LMs (e.g. deregulated (clonal) proliferation, re-wiring of EC metabolism, de-differentiation);
  • Identify novel causative gene mutations in the human FOXO genes;
  • Validate FOXO expression / (subcellular) localization as diagnostic and therapeutic (bio-)markers in patients with VMs and / or LMs.

Secondments:

  • AstraZeneca
  • de Duve Institute
  • Uppsala University