• Dr. Yujin Zhang, PhD

    I am a well-trained molecular and cellular biologist with extensive experience in working with genetically modified mice. I have a broad interest and background in hematology with specific training and expertise in translational studies. I have played a key role in the development of sickle cell disease (SCD) research in our laboratory. Using a high-throughput metabolomics screen, we found that adenosine, 2,3-BPG and sphingosine-1-phosphate (S1P) levels are elevated in the blood of SCD transgenic mice. These findings led us to discover that elevated adenosine signaling through the erythrocyte A2B adenosine receptor promotes sickling by inducing 2,3-BPG production, release of oxygen from HbS, deoxyHbS polymerization and sickling. Additional studies revealed that adenosine signaling via the erythrocyte A2B adenosine receptor also stimulated the production of sphingosine-1-phosphate (S1P) by activating sphingosine kinase 1 and that elevated S1P contributes to sickling. Lowering adenosine concentrations or blocking the activation of A2B receptors reduced sickling, hemolysis and tissue injury in SCD transgenic mice. Translational studies showed that adenosine, 2,3-BPG and S1P concentrations were elevated in the blood of individuals with SCD. Our results suggest that lowering adenosine or interfering with adenosine signaling with A2B receptor antagonists may be effective mechanism-based therapies for preventing sickling and hemolysis in individuals with SCD and ultimately for reducing the life-threatening complications associated with this genetic disease. The adenosine activated erythrocyte signaling pathways we discovered promote increased production of 2,3-BPG in erythrocytes and the release of O2 from Hb. Our published research shows that activation of these pathways is detrimental for individuals with SCD because their mutation causes deoxyHbS for form insoluble polymers that contribute to sickling. Normal deoxyHb does not form insoluble polymers. Our recent published studies revealed these same erythrocyte signaling pathways that are harmful for individuals with SCD are beneficial for normal humans adapting to hypoxia.

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