Identification of Therapeutic Targets That Reduce VLA-4 Adhesion-mediated Vaso-occlusive Episodes in Sickle Cell Disease

Urvashi Thongam 1, David Kakhniashvili 2, Steven Goodman 2, Jennell White 1,3 Department of Pharmacology 1, Wayne State University School of Medicine, 540 E Canfield St, Detroit, MI 48201; Proteomics & Metabolomics Core 2, University of Tennessee Health Science Center, 800 Madison Ave, Memphis, TN 38103; Carman and Ann Adams Department of Pediatrics 3, Wayne State University School of Medicine, Children's Hospital of Michigan, 3901 Beaubien Street, Detroit, MI 48201

Red blood cell (RBC) adhesion contributes to morbidity and mortality in sickle cell disease (SCD) by causing frequent and unpredictable vaso-occlusive episodes (VOEs). Hydroxyurea (HU), the mainstay therapy for SCD, reduces the frequency of VOEs, in part, by decreasing adhesion receptor expression and red cell-endothelial interactions. Very late antigen-4 (VLA-4), the most characterized adhesion receptor in SCD, is highly expressed on reticulocytes (immature RBCs) from SCD patients with frequent VOEs and decreased in HU-treated patients. VLA-4-dependent adhesive interactions are rapidly and reversibly modulated by cell signaling pathways in white blood cells and other inflammatory diseases however these mechanisms are not well defined in RBCs or SCD. Preliminary data from our lab indicate that VLA-4-mediated adhesion is decreased within minutes of HU treatment, suggesting rapid, erythroid cell signaling pathways may be involved. Using mass spectrometry (MS), we identified a novel approach to elucidate HU- and erythroid-signaling pathways that modulate VLA-4 function in sickle reticulocytes to aid in the development of alternative therapies to reduce VOEs in SCD. Post-acquisition analysis of raw MS data will identify VLA-4 protein interactions in SCD patients on/off HU therapy.

Additional Abstract Information

Presenter: Urvashi Thongam

Institution: Wayne State University

Type: Poster

Subject: Biochemistry

Status: Approved

Time and Location

Session: Poster 1
Date/Time: Mon 1:30pm-2:30pm
Session Number: 2174