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 outstanding resources, including the Children's Hospital of Philadelphia (CHOP) Cancer Center, the UPENN Clinical and Translational Research Center, Center for Clinical Epidemiology and Biostatistics, and the CHOP Cancer Survivorship Program. Accordingly, the candidate has assembled and will be guided by a renowned multidisciplinary Advisory Committee with expertise in epidemiology, biostatistics, oncology, endocrinology, and survivorship. The revised career development plan includes: (1) advanced epidemiology and biostatistics coursework selected to align with her career plan (e.g. longitudinal data analysis, clinical trial design, and survival analysis), (2) participation in the Childhood Cancer Survivor Study working groups for research activity, and (3) preparation of multiple peer-reviewed grants during the award to secure support for pilot and feasibility studies of potential interventions, while conducting research during the award period. The applicant's mentor is an NIH K24-funded senior investigator with expertise in bone health and body com- position in varied chronic diseases. The candidate's long-term career goal is to become a physician-scientist who conducts randomized clinical trials to treat the complications of childhood cancer therapy, and to provide expert clinical care for cancer survivors. This career development plan will build upon her knowledge base and epidemiology skills to complement the mentored research experience and will provide the foundation needed for her research focus in outcome and intervention trials in the field of Childhood Cancer Survivorship.
Hematopoietic stem-cell transplantation (HSCT) is an established treatment for benign and malignant hematologic diseases in children. With growing number of survivors, the focus of medical attention has turned to identification and prevention of long-term complications in survivors of childhood HSCT such as bone deficits, abnormal body composition, insulin resistance, and the metabolic syndrome. The mechanisms, evolution, and clinical significance of early and late metabolic and skeletal complications after childhood HSCT have not been established and the focus of this proposal.
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|Mostoufi-Moab, Sogol; Magland, Jeremy; Isaacoff, Elizabeth J et al. (2015) Adverse Fat Depots and Marrow Adiposity Are Associated With Skeletal Deficits and Insulin Resistance in Long-Term Survivors of Pediatric Hematopoietic Stem Cell Transplantation. J Bone Miner Res 30:1657-66|
|Mostoufi-Moab, Sogol; Isaacoff, Elizabeth J; Spiegel, David et al. (2013) Childhood cancer survivors exposed to total body irradiation are at significant risk for slipped capital femoral epiphysis during recombinant growth hormone therapy. Pediatr Blood Cancer 60:1766-71|
|Mostoufi-Moab, Sogol; Ginsberg, Jill P; Bunin, Nancy et al. (2012) Bone density and structure in long-term survivors of pediatric allogeneic hematopoietic stem cell transplantation. J Bone Miner Res 27:760-9|