Skeletal Health and Bone Marrow Composition in Adolescents with Crohn’s Disease

项目摘要 克罗恩病(CD)儿童通常骨密度(BMD)低，骨结构改变， 导致骨骼脆性增加。而儿童和青少年患者的骨形成受到影响 在诊断为CD时，调解这些疾病相关并发症的因素仍然知之甚少。 这是为年轻的CD患者确定积极措施和治疗方法的关键机会。这个 大多数骨量是在青春期后期通过加速骨转换而获得的，包括骨 形成和吸收。未能达到峰值骨量会增加终生骨质疏松的风险。 在正常骨骼发育过程中，造血(红)骨髓转化为富脂(黄)骨髓 健康的儿童和青少年。促进早产红骨髓向黄骨髓转化的条件 --可能还有它的可逆性--是患有CD的青年患者骨健康缺陷的核心原因。.的存在 青少年和成人的骨髓脂肪增加与生物力学强度降低有关， 对骨折风险的影响。在其他儿科疾病中，激素环境可以改变间充质干细胞。 优先分化为脂肪细胞，而不是成骨细胞，从而影响成骨。我们将研究 初诊CD的青少年在基线和一年后评估CD炎症的影响 骨髓脂肪活性、骨密度、骨转换标志物，并与外周血液免疫参数相关。 本项目是一项前瞻性的纵向病例对照研究，目的如下：(1)使用磁力 磁共振成像(MRI)、双能X射线吸收法(DXA)和外周定量计算机 体层摄影术(PQCT)，评估骨髓成分，面积和体积骨密度的青少年，新的- 诊断为CD并与健康匹配的对照组进行比较；(2)一次性检测骨髓脂肪和骨密度的变化 诊断后一年，CD患者与健康匹配对照组的比较，并调查 骨髓脂肪、骨密度和身体成分之间的关系；以及(3)评估 CD患者的骨形成受损，我们将研究骨转换标志物和免疫 细胞/分子参数及其与骨密度和骨髓脂肪的关系。 戈登博士的职业目标是成为一名独立的临床研究人员，应用最先进的研究 方法探讨儿科骨健康的临床相关问题。在K23颁奖期间，戈登博士将获得 通过正规教学课程相结合的临床和转化性研究的必备技能， 参加研讨会和会议，个性化指导，以及实践研究体验 波士顿儿童医院和哈佛医学院的支持环境。她将由以下人员指导 在炎症性肠病以及骨骼和矿物质代谢领域的领先研究人员。总而言之， 这项研究将利用最先进的工具来研究一种未被研究的疾病的新机制 作为一名独立内科科学家发展戈登博士职业生涯的基础。

Project Summary Children with Crohn’s disease (CD) often have low bone mineral density (BMD) and altered bone structure, resulting in increased skeletal fragility. While bone formation is compromised in pediatric and adolescent patients at diagnosis with CD, the factors mediating these disease-related complications remain poorly understood and represent a critical opportunity to identify proactive measures and therapies for young patients with CD. The majority of bone mass is acquired by late adolescence through the acceleration of bone turnover, including bone formation and resorption. A failure to achieve peak bone mass increases the lifetime risk of osteoporosis. Hematopoietic (red) bone marrow converts to lipid-rich (yellow) marrow during normal skeletal development in healthy children and adolescents. Conditions that accelerate the conversion of premature red to yellow marrow - and possibly its reversibility - are central to the deficits in bone health in youth with CD. The presence of increased marrow fat in adolescents and adults is associated with reduced biomechanical strength, with implications for fracture risk. In other pediatric diseases, the hormonal milieu can alter mesenchymal stem cells to differentiate preferentially into adipocytes over osteoblasts, compromising osteogenesis. We will examine adolescents with newly-diagnosed CD at baseline and one year later to evaluate the impact of CD inflammatory activity on marrow fat, BMD, bone turnover markers, and to correlate with peripheral blood immune parameters. This project is a prospective, longitudinal, case-control study with the following aims: (1) Using magnetic resonance imaging (MRI), dual-energy x-ray absorptiometry (DXA), and peripheral quantitative computed tomography (pQCT), evaluate bone marrow composition, areal and volumetric BMD in adolescents with newly- diagnosed CD and compare to healthy matched controls; (2) Examine changes in marrow fat and BMD at one year after diagnosis, across patients with CD versus in healthy matched controls, and investigate the associations between marrow fat, BMD, and body composition; and (3) To evaluate the mechanism of compromised bone formation in patients with CD, we will investigate bone turnover markers and immune cellular/molecular parameters and their associations with BMD and marrow fat. Dr. Gordon’s career goal is to become an independent clinical researcher, applying state-of-the-art research methods to clinically relevant problems in pediatric bone health. During the K23 award, Dr. Gordon will acquire the requisite skills in clinical and translational investigation through a combination of formal didactic coursework, attendance at seminars and conferences, personalized mentoring, and hands-on research experience in the supportive environment of Boston Children’s Hospital and Harvard Medical School. She will be mentored by leading investigators in the fields of inflammatory bowel disease and bone and mineral metabolism. In summary, this study will utilize state-of-the-art tools to investigate novel mechanisms of disease in an understudied population, and serve as a basis for developing Dr. Gordon’s career as an independent physician scientist.