Sickle Cell Disease is an autosomal recessive genetic disorder, which affects at least 100,000 Americans and millions world-wide. Sickle Cell Anemia (SCA) is the most common form of SCD that is caused by a substitution of hydrophobic valine (Val) for hydrophilic glutamic acid (Glu) at the sixth position in the beta globin chain. Under hypoxic conditions, the mutated hemoglobin (HbS) undergoes reversible polymerization to form long fibers, which cause RBCs to sickle. It is believed that sickle RBCs (sRBCs) get trapped in small blood vessels along with leukocytes and platelets to cause vaso-occlusion. Vaso-occlusion is the predominant pathophysiology responsible for the acute pain crisis and emergency medical care among SCD patients. Acute Chest Syndrome (ACS) is a form of acute lung injury (ALI) and a leading cause of morbidity among SCD patients. SCD patients hospitalized with acute pain crises often develop ACS within the next few days suggesting a role for vaso-occlusion in lung injury. However, the exact etiological mechanism that triggers ACS is still elusive and the available treatment is primarily supportive.
The Sundd lab aspires to elucidate the molecular and biophysical mechanism of leukocyte-platelet-endothelium interaction during inflammation and how these events contribute to Vaso-Occlusive Crisis (VOC) and ACS in SCD. To achieve this we are using a multi-scale integrative physiologic approach, which involves in vivo Multi-Photon Excitation (MPE) fluorescence microscopy in transgenic and knock-in mice, microfluidic assays with patient blood, total internal reflection fluorescence (TIRF) microscopy, structured illumination microscopy (SIM), laser confocal microscopy, electron microscopy and various biochemical approaches. This multi-scale approach enables us to address the link between the pathophysiology of ACS affecting the lung (macro-level response) to the aberrant cellular events (micro-level response) driving the vaso-occlusion and the molecular interactions (nano-level response) enabling those cellular events. Identifying the molecular mechanism of vaso-occlusion in the lung will inspire therapeutics to prevent ACS in SCD patients.
The Vascular Medicine Institute (VMI) at the University of Pittsburgh-School of Medicine provides excellent opportunities for career development to post-doctoral scholars and graduate students. VMI has a strong training program for outstanding postdoctoral candidates aspiring to make a career in vascular/inflammation biology. Interested candidates are encouraged to contact Dr. Sundd by email.