Sickle cell disease is an autosomal recessive genetic disorder that is caused by a single point mutation at the 6th position of the β-globin gene, resulting in the substitution of valine for β-glutamate-6 amino acid producing hemoglobin S (HbS). When deoxygenated, HbS polymerizes intracellularly producing sickle cells that adhere to vessel walls causing blockages (vaso-occlusions). Polymerization is initiated when the substituted valine binds in the hydrophobic pocket of deoxyhemoglobin. Vaso-occlusive crises constrict blood flow resulting in hypoxia and pain. Sickle cell crisis causes severe pain from organ hypoxia, often requiring hospitalization. Recently, drugs like Voxelotor and Alizarin have been developed to reduce HbS polymerization by stabilizing hemoglobin in the oxygenated state and crizanlizumab, a monoclonal antibody against P-selectin, reduces RBC binding to vessel walls. Curative treatments like bone marrow transplant, gene transfer and experimental gene editing are available for the more severe patients but are expensive options. We are testing different isoforms of valine to determine if valine can bind the hydrophobic pocket to prevent polymerization. We are using the hemoglobin solubility assay (Sickle Confirm test) as our method to detect a reduction in polymerization. L and D-valine were introduced to deoxyhemoglobin along with the buffer solution as controls in concentrations ranging from 1.0x10-4 to 8.0x10-4. Results thus far suggest that there is not a significant impact on polymerization when introducing isoforms of valine to deoxygenated HbS through Sickle Confirm methods. Further experimentation with different concentrations, amino acids or short polypeptides will be used to evaluate polymerization inhibition. 

Dr. Tim Randolph allows students to explore their passion for research and medicine through his lab in a multitude of ways. Research students are able to develop critical thinking skills, appreciate the complexity of research, and develop interpersonal skills with peers and Dr. Randolph as their mentor. In addition, his patients and generosity to share knowledge with others has made a tremendous impact on others. Under his mentorship, students connect real world situations, such as the sickle cell crisis in Haiti, to clinical lab experience.