The role of procoagulant FVIII in sinusoidal endothelial cell reprogramming
Endothelial cells (EC) respond to various stress to maintain vascular homeostasis, and a disrupted response is associated with cirrhosis. We have recently found that loss of procoagulant factor VIII can accelerate cirrhosis by changing endothelial reprogramming. In this project we will focus on the mechanisms by which sinusoidal endothelial cells are affected in FVIII knock out murine model using state of the art imaging, biochemistry and molecular biology techniques. This project will be useful to dissect the mechanism of underlying EC responses to FVIII loss, and to investigate the influence of coagulation during liver homeostasis and disease.
Liver in Hemophilia
Hemophilia A is a rare X-linked recessive bleeding disorder that is caused by the deficiency or absence of factor VIII (FVIII). Since the etiology of hemophilia is heterogeneous, it is hard to study the pathophysiology of hemophilia A associated co-morbidities. However, there are reports of liver morbidities associated with Hemophilia-A. Hemophilia patients are frequently considered for a liver transplantation due to cirrhosis and related complications. There are also increasing reports on severe hemophilia associated portal hypertension in patients. The current treatment for hemophilia induced liver morbidity is primarily supportive, and the molecular mechanism is largely unknown, suggesting that preventive therapies based on the improved understanding of the molecular pathways that enable Hemophilia induced cirrhosis and portal hypertension are needed. In this project using a FVIII deficient mouse model we will identify the molecular mechanism of hepatobiliary injury in hemophilia.