Pharmacogenetics of Pediatric Sickle Cell Disease

Children'S Mercy Hosp (Kansas City, Mo), Kansas City MO

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): This investigator proposes a comprehensive program for development as a clinical investigator which reflects her interest in pediatric clinical pharmacology and pediatric hematology/oncology. The long-term goal of this investigator is to understand how genetic polymorphisms affect the pathogenesis of sickle cell disease and response to treatment. Under the mentorship of well-established, nationally and internationally recognized experts in the areas of pharmacogenetics, pediatrics and pediatric sickle cell disease at Indiana University (IU), as well as collaboration with other experts in the fields of nitric oxide biology and sickle cell disease, this applicant will pursue a focused clinical research project related to the pharmacogenetics of pediatric sickle cell vaso-occlusive crisis and will receive both didactic and practical instruction in all aspects of clinical investigation through the IU K30 program. Painful vaso-occlusive crisis, the most common complication in children with sickle cell disease, exhibits a large amount of variability in clinical course and response to treatment that remains unexplained. This application addresses both the mechanisms involved in the pathogenesis of vaso-occlusive crisis as well as the pharmacologic barriers to successful treatment with hydroxyurea, a drug that targets disease pathogenesis. Two specific aims will test the following hypotheses: (1) that genetic polymorphisms in the endothelial nitric oxide synthase (eNOS) gene affect nitric oxide availability and the pathogenesis of vaso-occlusive crisis, and (2) that genetic variants influence the pharmacokinetics and pharmacodynamics of hydroxyurea. The results from these investigations will lead to additional research directed at establishing the link between disease pathogenesis and treatment in children with sickle cell disease.