Molecular mechanism of Sickle cell hepatic Crisis
Intravital imaging of control mouse liver showing continuous blood flow through the hepatic sinusoids at baseline
Intravital imaging of sickle mouse liver with blood stasis (black region) suggestive of ischemia at baseline
NIH-NIDDK-K01 funded research: Hepatic crisis affects 10-40% of hospitalized sickle cell disease (SCD) patients, which is characterized by liver injury , inflammation, iron accumulation and cholestasis that can progress to fatal liver failure. The current treatment for hepatic crisis in SCD is primarily supportive, and the molecular mechanism is largely unknown. This project will determine novel inflammatory and nuclear receptor signaling pathways that may serve as useful therapeutic targets for the future treatment of Sickle cell hepatobiliary injury.
The effect of chronic P-selectin deficiency in sickle cell disease
ASH Junior Faculty Scholar Award 2022: P-selectin inhibition has been shown to prevent vaso-occlusive events in SCD patients, however, the chronic effect of P-selectin inhibition in SCD remains to be determined. We are using quantitative liver intravital microscopy , molecular biology and biochemical techniques in our recently generated P-selectin deficient SCD mice to evaluate the effect of chronic P-selectin deficiency in liver and spleen. Using quantitative liver intravital microscopy we have recently shown that chronic P-selectin deficiency attenuates liver ischemia, but fails to prevent hepatobiliary injury (Blood, 2021). Remarkably, we find that this failure in resolution of hepatobiliary injury in P-selectin deficient SCD mice is associated with the increase in cellular senescence and reduced epithelial cell proliferation in the liver. These findings highlight the importance to investigate the long-term effects of chronic P-selectin inhibition therapy on liver pathophysiology in SCD patients.
Molecular mechanism and therapeutic implications of hepatic iron homeostasis in sickle cell disease.
Chronically transfused SCD patients develop severe iron overload in liver, heart, spleen, and endocrine organs with increased expression of inflammatory markers and mortality. Similarly increased hemolysis due to haemoglobin polymerization leads to continuous accumulation of iron particles in SCD. However, baseline changes in hepatic iron metabolism and homeostasis due to ongoing hemolysis is relatively less understood in SCD. Under normal physiological conditions iron is predominantly stored in hepatocytes as ferritin form. Apart from hepatocytes, kupffer cells (hepatic macrophages) are also involved in iron metabolism through engulfing and phagocytosing iron particles and promoting iron homeostasis in the liver. Previous studies have shown that iron accumulation from increased hemolysis associated with SCD, activated macrophages to an M1-like proinflammatory phenotype via ROS and TLR4-controlled signaling which was preventable by heme scavengers or iron chelators. Although macrophage activation is known phenotype of SCD, the role of tissue specific macrophages in SCD induced chronic organ injury initiation, progression or maintenance is not well understood. Similarly how the hepcidin-ferroportin axis work in hepatocyte and macrophages in SCD liver is also not known. We are interested in understanding these molecular interactions using mouse models, basic biochemistry , molecular biology and imaging techniques.