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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23DK082012-03
Application #
7872964
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Program Officer
Podskalny, Judith M,
Project Start
2008-07-01
Project End
2013-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
3
Fiscal Year
2010
Total Cost
$146,750
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
DeBoer, Mark D; Lee, Arthur M; Herbert, Kirabo et al. (2018) Increases in IGF-1 After Anti-TNF-? Therapy Are Associated With Bone and Muscle Accrual in Pediatric Crohn Disease. J Clin Endocrinol Metab 103:936-945
Stein, Ronen; Lee, Dale; Leonard, Mary B et al. (2016) Serum Infliximab, Antidrug Antibodies, and Tumor Necrosis Factor Predict Sustained Response in Pediatric Crohn's Disease. Inflamm Bowel Dis 22:1370-7
DeBoer, Mark D; Thayu, Meena; Griffin, Lindsay M et al. (2016) Increases in Sex Hormones during Anti-Tumor Necrosis Factor ? Therapy in Adolescents with Crohn's Disease. J Pediatr 171:146-52.e1-2
Griffin, Lindsay M; Thayu, Meena; Baldassano, Robert N et al. (2015) Improvements in Bone Density and Structure during Anti-TNF-? Therapy in Pediatric Crohn's Disease. J Clin Endocrinol Metab 100:2630-9
DeBoer, Mark D; Weber, David R; Zemel, Babette S et al. (2015) Bone Mineral Accrual Is Associated With Parathyroid Hormone and 1,25-Dihydroxyvitamin D Levels in Children and Adolescents. J Clin Endocrinol Metab 100:3814-21
Augustine, Marianne V; Leonard, Mary B; Thayu, Meena et al. (2014) Changes in vitamin D-related mineral metabolism after induction with anti-tumor necrosis factor-? therapy in Crohn's disease. J Clin Endocrinol Metab 99:E991-8
Tsampalieros, Anne; Lam, Carol K L; Spencer, Jenna C et al. (2013) Long-term inflammation and glucocorticoid therapy impair skeletal modeling during growth in childhood Crohn disease. J Clin Endocrinol Metab 98:3438-45
Prosnitz, Aaron R; Leonard, Mary B; Shults, Justine et al. (2013) Changes in vitamin D and parathyroid hormone metabolism in incident pediatric Crohn's disease. Inflamm Bowel Dis 19:45-53
Zahm, Adam M; Thayu, Meena; Hand, Nicholas J et al. (2011) Circulating microRNA is a biomarker of pediatric Crohn disease. J Pediatr Gastroenterol Nutr 53:26-33
Thayu, Meena; Denson, Lee A; Shults, Justine et al. (2010) Determinants of changes in linear growth and body composition in incident pediatric Crohn's disease. Gastroenterology 139:430-8