The mission of St. Jude Children's Research Hospital (SJCRH) is to find cures for children with catastrophic illnesses through research and treatment, a mission that is directly relevant to the 700 children and adolescents cared for in our Comprehensive Sickle Cell Center. We seek to offer a broad range of therapeutic options. Namely, supportive care, chronic transfusion, drug therapy or stem cell transplantation, to our patients and in so doing to implement effective clinical research protocols to evaluate these options. Project N, the Network (Inter-Center) Proposal, seeks to test combination """"""""chemotherapy"""""""" for reducing the frequency of pain crises through a Phase III trial of hydroxyurea and magnesium vs. hydroxyurea and placebo in pediatric and adult patients. In Project 1, a formal Phase I trial of magnesium will be conducted in pediatric patients, and then a Phase II trial will examine the effect of this combination on prevention and/or reversal of central nervous system abnormalities, on red blood cell properties and on nutritional status. In Project 2, we seek to test the feasibility of using parental donors for haploidentical stem cell transplantation to extend potentially curative therapy to more children with sickle cell disease. Project 3, utilizes a murine model of sickle cell disease to explore pathogenesis of pneumococcal infection in the children followed in our Center to examine the effects of penicillin prophylaxis, vaccines and specific antimicrobial therapy on the frequency of antibiotic tolerance and/or resistance. In Project 4, lentiviral vectors designed to express a gamma-globin gene at high levels will be optimized in a murine model of sickle cell disease and we will test the concept of in vivo drug selection to amplify a minority, genetically modified hematopoietic population to achieve effective gene therapy. Project 5 is focused on understanding the regulatory mechanisms that modulate the relative levels of expression of the gamma- and Beta-globin genes in maturing erythroblasts. Activities are integrated through the functions of the Clinical Core, a Patient Services Core and a Central Nervous System Assessment Core. Our Sickle Cell Scholars will have the opportunity to develop a translational research career through mentoring with a focus in the clinic and/or laboratory. Thus our Comprehensive Sickle Cell Center effectively integrates clinical, translational and basic research and thereby fosters multidisciplinary collaborations directed toward the goal of finding effective therapy and ultimately a cure for sickle cell disease.
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