DESCRIPTION (provided by applicant): Hematopoietic stem cell transplantation (HSCT) is an established treatment for benign and malignant hemato- logic diseases in children. As mortality continues to decline, the focus of clinical care has turned to the identification and prevention of
treatment-related complications in survivors of childhood HSCT. The overarching goal of this proposal is to identify therapeutic targets, and inform future clinical trials to treat these complications. The applicant recently published the first comprehensive studies of trabecular bone mineral density (BMD), cortical structure, and body composition in 55 long-term survivors of childhood HSCT. Despite completion of therapy years prior, these recipients had markedly increased whole body fat mass, decreased lean mass, and substantial deficits in trabecular BMD and cortical dimensions compared with >650 healthy reference participants. These findings herald significant risks for skeletal fragility and the metabolic syndrome, with substantil impact on health-related quality of life. Longitudinal studies are imperative to determine the onset and progression of these abnormalities, and to identify risk factors and therapeutic targets. This proposal will characterize changes in bone health, body composition, and fat distribution after childhood HSCT, and determine associations with insulin resistance, the metabolic syndrome, and bone deficits. The study has two primary components. The first component will examine early changes in skeletal parameters and body composition in a cohort of 60 newly transplanted pediatric HSCT recipients (short-term survivors) over two years. The second component will extend the applicant's recent study of long-term survivors to ex- amine changes in bone deficits, excess adiposity, and reduced muscle mass, and to identify risk factors for deterioration in these outcomes. The study will also examine fat distribution, insulin resistance, and the meta- bolic syndrome in both cohorts. A potential explanation for the bone deficits in HSCT survivors stems from the inverse relation between bone and fat formation within the bone marrow cavity, where hormones and transcription factors regulate mesenchyme stem cell (MSC) differentiation into osteoblasts or osteocytes. Since the original K07 application,
the applicant was awarded a Foundation grant to evaluate marrow adipose tissue in HSCT survivors. The revised proposal now includes a highly innovative MR-spectroscopy measure of vertebral marrow adipose tissue and micro-MRI measures of bone microarchitecture in long-term HSCT survivors. These findings will provide significant insight into the fat-bone axis and its
contribution to the bone and metabolic complications following HSCT. These data will be critical for the identification of potential interventions to target MSC differentiation, enhance bone formation, and reduce adiposity, and will form the basis of the applicant's future R01 proposals. The applicant is a dual certified pediatric endocrinologist and oncologist with advanced epidemiology training. Her research program is focused on bone, body composition, and metabolic abnormalities in survivors of childhood malignancies. In the interim since original submission of this proposal, the candidate completed a study on recovery of bone density and structure in children and adolescents after completion of therapy for acute lymphoblastic leukemia (manuscript under review), and a second study examining skeletal complications of growth hormone therapy in cancer survivors after radiation compared to children treated with growth hormone for idiopathic growth hormone deficiency (manuscript in preparation). The proposed research will provide the necessary experience in leading a complex longitudinal study in critically ill patients after HSCT, and will allow the candidate to pursue further trainin and support critical to her research and career development. The applicant will draw on o |