Investigating Platelet Immune Mechanisms in Sickle Cell Disease

PROJECT SUMMARY/ABSTRACT This proposal describes a rigorous training program for the career development of Dr. Sean Gu, an academic clinical pathologist specializing in hematopathology. The proposed research builds upon the candidate’s previous research and clinical experiences. Under the guidance of a multidisciplinary mentorship team led by his primary mentor, Dr. John Hwa, the comprehensive training plan outlined in this proposal will provide Dr. Gu with the knowledge and skills necessary to become a successful and independent physician-scientist. Sickle cell disease (SCD) is one of the most common inherited blood disorders with an estimated 300,000 infants born globally each year, and in the United States alone, affecting approximately 100,000 individuals. SCD is a multisystem disorder characterized by remarkable phenotypic complexity with debilitating complications. Excessive platelet activation has been consistently observed in SCD patients; however, clinical trials have failed to show significant benefit of conventional antiplatelet therapies in preventing SCD vaso-occlusive disease. Therefore, a better understanding of the cellular and molecular mechanism that drive platelet alterations in SCD can lead to more selective and effect strategies. In this proposal, the candidate proposes to employ novel high-throughput methods to characterize the heterogeneous states of platelets in SCD. By analyzing blood specimens collected from SCD patients and utilizing transgenic mouse models of SCD, the candidate will address 1) how distinct platelet subpopulations contribute to SCD vaso-occlusive disease and 2) investigate specific immunothrombotic pathways and mechanisms of platelet activation and dysfunction in SCD. The knowledge gained from these studies will advance our understanding of SCD disease pathogenesis and provide opportunities for developing novel targeted therapies.