The role of hemolysis in sickle cell disease organ injury

Hemolysis is a key characteristic of sickle cell disease (SCD) that contributes to the disease pathogenesis and clinical heterogeneity. In SCD, cell free hemoglobin and its byproducts (heme and iron) cause vasculopathy as well as a slew of clinical consequences, including liver failure. Although liver injury affects up to ~40% of hospitalized SCD patients, therapeutic approaches to prevent liver injury in SCD are limited.

In the Pradhan-Sundd lab we are interested in understanding the molecular (signalling) mechanism of hemolysis induced acute and chronic liver injury. We are also investigating the processes of hepatic hemoglobin, heme, and iron clearance in SCD.

Sinusoidal endothelium driven liver directed gene therapy in hemophilia

Hemophilia A is an X-linked recessive bleeding disorder caused by the absence of coagulation factor- VIII (FVIII). Individuals who are affected are at risk of spontaneous bleeding into joints which can be life threatening. Recent advances in liver-directed gene transfer suggest that gene therapy can successfully treat hemophilia A. FVIII is produced in the liver sinusoidal endothelial cells. Thus, liver sinusoidal endothelial cell viability and functioning are important for successful liver directed gene transfer in Hemophilia. We have recently shown liver sinusoidal endothelial maladaptive structural changes in FVIII-deficient mice and their deleterious impact on the efficacy of liver-directed gene transfer. Abnormal endothelial function was recently recognized in patients with hemophilia A. Our current research focuses on investigating the molecular mechanisms that contribute to the loss of endothelial fenestration in individuals with FVIII deficiency, and how this loss impacts liver-directed gene therapy in patients with hemophilia.