B1 Goerdt

Organ-specific differentiation of hepatic sinusoidal endothelium (HSEC) as analyzed by our group is characterized by scavenger receptors stabilin-1/2, by a special net of microtubules along which clathrin-coated, stabilin1/2+ vesicles travel, and by selective expression of wnt2 acting as an autocrine growth factor cross-stimulating the VEGF pathway. As HSEC rapidly dedifferentiate and become dysfunctional in culture and in hepatic disease, we aim at defining HSEC differentiation and remodeling using gene profiling of normal / cultured HSEC and of HSEC from ethanol-treated animals including stab-1/2-/- mice. Novel HSEC-specific molecules will be over-expressed in lung microvascular endothelial cells to identify target genes and to achieve sinusoidal re-programming. Dysfunctional HSEC will be analyzed by studying epigenetic regulation of HSEC-specific indicator gene promoters and by epigenetic profiling. Finally, targeting strategies will be developed to rescue HSEC from dysfunction.