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

患有克罗恩病的青少年的骨骼健康和骨髓成分

• 批准号: 10740272
• 负责人: Rebecca Judith Gordon
• 金额: $ 19.64万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-04 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740272
• 关键词: Acceleration; Address; Adipocytes; Adolescence; Adolescent; Adult; Anorexia Nervosa; Biomechanics; Body Composition; Bone Density; Bone Marrow; Bone Resorption; Bone structure; Boston; Case/Control Studies; Cells; Child; Childhood; Chronic; Clinical; Crohn' s disease; Data; Diagnosis; Disease; Dual-Energy X-Ray Absorptiometry; Failure; Fatty acid glycerol esters; Fracture; Functional disorder; Goals; Health; Hematopoietic; Hormonal; Hormonal Change; Imaging Techniques; Immune; Immune system; Inflammatory; Inflammatory Bowel Diseases; Knee; Knowledge; Lipids; Location; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Marrow; Measures; Mediating; Mentored Patient-Oriented Research Career Development Award; Mentors; Mesenchymal Stem Cells; Metabolism; Minerals; Molecular; Molecular Profiling; Newly Diagnosed; Obesity; Osteoblasts; Osteogenesis; Osteoporosis; Patients; Pediatric Hospitals; Peripheral; Phenotype; Physicians; Population; Preventive; Red Marrow; Research Methodology; Research Personnel; Scientist; Screening procedure; Skeletal Development; Translational Research; X-Ray Computed Tomography; Yellow Marrow; Youth; adolescent patient; bone; bone fragility; bone geometry; bone health; bone mass; bone turnover; career; clinical care; clinical investigation; clinically relevant; experience; fracture risk; hands on research; high risk; improved; insight; lean body mass; lifetime risk; medical schools; new therapeutic target; novel; osteoimmunology; pediatric patients; peripheral blood; premature; prospective; skeletal; skills; supportive environment; symposium; tool; treatment effect

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.

项目摘要 克罗恩病（CD）的儿童通常具有低骨矿物质密度（BMD）和骨结构改变， 导致骨骼脆弱性增加。小儿和青春期患者骨骼形成却受到损害 在用CD诊断时，介导这些与疾病相关并发症的因素保持不佳，并且 代表了为CD年轻患者确定积极措施和疗法的关键机会。这 大多数骨骼质量是通过骨转换加速的青春期后期获得的，包括骨骼 形成和分辨率。未能达到峰值骨质量会增加骨质疏松症的寿命风险。 造血（红色）骨髓在正常骨骼发育过程中转化为富含脂质的（黄色）骨髓 健康的儿童和青少年。加速过早红骨髓的转化的条件 - 并且可能的可逆性 - CD青年人骨骼健康的防御性至关重要。存在 青少年和成年人中骨髓脂肪增加与生物力学强度降低有关，与 对断裂风险的影响。在其他小儿疾病中，激素环境可以改变间充质干细胞 更优选地将成骨细胞的脂肪细胞区分为脂肪细胞，从而损害成骨。我们将检查 基线和一年后，具有新诊断CD的青少年评估CD炎症的影响 对骨髓脂肪，BMD，骨转换标记的活性，并与外周血免疫参数相关。 该项目是一项前瞻性，纵向，病例对照研究，其目的是：（1）使用磁性 共振成像（MRI），双能X射线绝对肽（DXA）和外围定量计算 层析成像（PQCT），评估新骨髓组成，面积和体积BMD 诊断CD并与健康匹配的对照相比； （2）检查骨髓脂肪和BMD的变化 诊断后的一年，跨CD与健康匹配对照的患者进行了研究，并研究了 骨髓脂肪，BMD和身体成分之间的关​​联； （3）评估 CD患者的骨形成破坏，我们将研究骨转换标记和免疫 细胞/分子参数及其与BMD和骨髓脂肪的关联。 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 小儿骨骼健康中临床相关问题的方法。在K23奖上，戈登博士将获得 通过正式的教学课程的结合，临床和翻译研究的必要技能， 参加下水道和会议，个性化心理和动手研究经验 波士顿儿童医院和哈佛医学院的支持环境。她将被考虑 炎症性肠病以及骨骼和矿物质代谢领域的主要研究人员。总之， 这项研究将利用最先进的工具来研究疾病的新机制 人口，是发展戈登博士作为独立物理科学家职业的基础。