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Research Abstracts Online
January 2009 - March 2010

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University of Minnesota Twin Cities
College of Pharmacy
Department of Experimental and Clinical Pharmacology

PI: Ramaiah Muthyala

Sickle Cell Disease—Therapeutics Development

Sickle cell disease (SCD) is a devastating hemoglobinopathy characterized by chronic hemolytic anemia with acute events such as vaso-occlusion, acute chest syndrome, and other problems and is a serious genetic disease that affects black people. Patients with acute manifestations may have prolonged and repeated hospitalizations leading to poor quality of life and profound psychological impact. SCD exhibits different phenotypes and are dependent on different issues, some genetic or epigenetic, and some seemingly apparently unrelated cellular phenomena.

Hemoglobin, a protein with a molecular weight of 66,000 consists of two alpha and two beta chains. The molecular defect of the homozygote sickle cell hemoglobin HbS occurs in the sixth amino acid residue from amino terminal in the beta chains of normal hemoglobin (HbA). The change occurs from glutamic acid to valine.
The project studies: the mechanism of abnormal adherence of sickle erythrocytes to endothelial cells, an event in the initiation and/or progression of vasoocclusive crisis; human erythrocytes signal transduction pathways; in silico screening of small molecule libraries as PKA, PDE5 inhibitors; RBCs signaling molecules such as basal cell adhesion molecules, intracellular adhesion molecules (ICAM)-4/LW, and integrin associated protein (IAP); and the promotion of bioavailability of nitric oxide.

The objective of this research is to understand the patho-physiology of SCD and to translate the knowledge into improved and more rapid development of newer therapies.