NF-κB signaling in brain endothelial cells

Description

During EAE, a model of multiple sclerosis, and stroke, endothelial upregulation of adhesion molecules and an increased permeability of the BBB are required for infiltration of immune cells into the brain. The fact that many of the adhesion molecules induced in endothelial cells are target genes of the transcription factor NF-κB suggests that NF-κB is activated in endothelial cells and promotes neuroinflammation. Partner 1 has developed a conditional approach for cell-specific gene deletion in brain endothelial cells. Using the mouse line Slco1c1-CreERT2, the key component p65 of the NF-κB complex will be deleted in brain endothelial cells. To test the efficacy of this approach, the induction of adhesion molecules and other inflammatory markers in brain endothelial cells will be investigated in p65-deficient mice. Furthermore, the tightness of the BBB will be tested in cooperation with partner 3. In p65-deficient endothelial cells partner 1 will investigate in vitro whether the adhesion and transmigration of T cells is affected employing techniques developed by partner 5. Then, the neurological deficit and histological signs of inflammation and demyelination will be quantified in a mouse model of stroke and EAE in cooperation with partner 12. To test how the infiltration of immune cells into the CNS is affected, flow cytometry will be performed.

Publications

  • Bargiotas P, Krenz A, Hormuzdi SG, Ridder DA, Herb A, Barakat W, Penuela S, von Engelhardt J, Monyer H, Schwaninger M (2011) Pannexins in ischemia-induced neurodegeneration.Proc Natl Acad Sci USA 108: 20772-7
  • Ridder DA, Lang MF, Salinin S, Röderer JP, Struss M, Maser-Gluth C, Schwaninger M (2011) TAK1 in brain endothelial cells mediates fever and lethargy. J Exp Med 208: 2615-23

Tasks and methodology

  • Culture of brain endothelial cells
  • Co-culture of endothelial cells and T cells
  • Stroke model
  • EAE model

Planned secondment

VU University Medical Center, Establishment of EAE model, University of Muenster, Regulation of barrier properties by NF-κB, 9 month