The candidate is young investigator in pediatric gastroenterology with advanced training in clinical epidemiology and a research focus on the musculoskeletal complications of pediatric Crohn disease (CD). The candidate proposes a comprehensive, interdisciplinary program that will provide her with the skills and experience necessary for her development into an independent clinical investigator in pediatric gastroenterology and epidemiology. Her career development will be guided by an outstanding team of established investigators in gastroenterology, nutrition, epidemiology, biostatistics and immunology. The training component includes formal coursework in immunology with a focus on osteoimmunology, and continued advanced coursework in epidemiology. During her fellowship, the candidate conducted preliminary studies in children with CD demonstrating marked deficits in muscle mass, bone density and structure, and markers of bone formation in the absence of glucocorticoid therapy. She hypothesized that these deficits were mediated by tumor necrosis factor (TNF)-ct. Consistent with this hypothesis, preliminary data in children undergoing therapy with a TNF-a inhibitor (infliximab) demonstrated significant short-term improvements in bone formation markers; the clinical significance of these changes is not known. Thus, this revised application includes a substantial body of preliminary data that demonstrates significant research productivity and supports the candidate's hypotheses. The proposed prospective longitudinal study will use advanced imaging techniques to assess bone density and structure and body composition in a cohort of 100 children and young adults initiating infliximab therapy. The revised aims of the study are to (1) identify determinants of short-term changes in biomarkers of bone turnover in children and young adults with CD over the 6 week infliximab induction interval, and (2) to determine if changes in bone biomarkers during induction therapy are associated with improvements in muscle mass, bone density and bone structure over 12 months. Relevance: Children and young adults with CD are at risk for osteopenia and cachexia. TNF-a inhibitors may serve as an anabolic therapy to improve bone health and body composition in CD. Completion of this study will provide the applicant with the data and experience needed to support subsequent independent proposals to improve musculoskeletal health in this high-risk population. ? ? ?
