Muscle & Bone Mass Changes after TNF-a Inhibition in Pediatric Crohn Disease

描述（由申请人提供）：该候选人是儿科胃肠病学的年轻研究者，在临床流行病学方面接受过高级培训，研究重点是儿童克罗恩病（CD）的肌肉骨骼并发症。候选人提出了一个综合的，跨学科的项目，这将为她提供必要的技能和经验，使她成为一名独立的儿科胃肠病学和流行病学临床研究者。她的职业发展将由一个由胃肠病学、营养学、流行病学、生物统计学和免疫学等领域的知名研究人员组成的优秀团队指导。培训部分包括免疫学的正式课程，重点是骨免疫学，以及流行病学的继续高级课程。在她的研究期间，候选人对患有乳糜病的儿童进行了初步研究，发现在没有糖皮质激素治疗的情况下，肌肉质量、骨密度和结构以及骨形成标志物明显不足。她假设这些缺陷是由肿瘤坏死因子(TNF)-ct介导的。与这一假设相一致，接受TNF-a抑制剂（英夫利昔单抗）治疗的儿童的初步数据显示，骨形成标志物的短期改善显著；这些变化的临床意义尚不清楚。因此，这一修订后的申请包括大量的初步数据，证明了显著的研究生产力，并支持候选人的假设。提出的前瞻性纵向研究将使用先进的成像技术来评估100名开始英夫利昔单抗治疗的儿童和年轻人的骨密度、结构和身体组成。修订后的研究目的是：(1)确定6周英夫利昔单抗诱导期儿童和青年CD患者骨转换生物标志物短期变化的决定因素；(2)确定诱导治疗期间骨生物标志物的变化是否与12个月内肌肉质量、骨密度和骨结构的改善有关。相关性：患有乳糜泻的儿童和年轻人有骨质减少和恶病质的风险。TNF-a抑制剂可以作为一种合成代谢疗法来改善CD患者的骨骼健康和身体成分。本研究的完成将为申请人提供所需的数据和经验，以支持随后的独立建议，以改善这一高危人群的肌肉骨骼健康。

Description (provided by Applicant): 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.