Research Summary

The critical role of microRNAs in placenta growth factor-induced vascular dysfunction in Sickle Cell disease

My research program aims to understand the molecular basis of the development of different pathological complications in sickle cell disease (SCD) patients and to develop the strategies to translate the laboratory research for the benefit of patients. SCD is a genetic disorder of hemoglobin mutation affecting millions worldwide. Among the multiple pathologies, the most important feature is recurring painful vaso-occlusive crisis (VOC), due to trapping of sickle RBC in tiny blood vessels in microvascular circulation, leading to end organ damage. While there have been many clinical studies and therapeutic interventions, we have had no therapeutic success till date in dealing with these complications. My scientific efforts of the past 5 years, have provided a totally novel approach and identified placenta growth factor (PlGF), a molecule released by sickle RBCs, causing abnormal activation of blood monocytes and vascular endothelial cells. I plan to continue my research efforts to further understand the pathologic role of PlGF and microRNAs in regulation of key adhesion molecules involved in abnormal adhesion of sickle RBCs to endothelial cells, an initial event leading to VOC. Such molecular discoveries coupled with validation of results in transgenic disease animal models and SCD patients will provide novel therapeutics and diagnostic biomarkers to deal with devastating complication of VOC in SCD.

Figure Legend: This simplified diagram illustrates the proposed research to address the critical role of Placenta growth factor (PlGF), released by sickle erythroid cells in regulation of crucial genes such as intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), Von Willebrand factor (vWF) and tissue factor (TF) in pulmonary microvascular endothelial cells through modulation in microRNAs expression. These genes play a key role in abnormal adhesion between sickle RBCs and vascular endothelium, which initiates the development of painful vaso-occlusive crises (VOC) leading to multiple organ damage in patients with sickle cell disease.