Sex Differences in Statural Growth Impairment in Pediatric Crohn's Disease: Part 2

项目总结/摘要 生长障碍是小儿克罗恩病的常见并发症。正常化 生长是疾病控制和克罗恩病治疗成功的标志。治疗 改善生长障碍和最终成年身高的策略目前是次优的。的 克罗恩病对生长的影响可能由许多因素介导，包括 炎症、遗传学、微生物组、营养和药物。的继续存在 增长障碍主要反映了对基础疾病的持续次优治疗， 克罗恩氏病特有的炎症。我们假设炎症 克罗恩病的特征对内分泌生长调节剂有更大的负面影响 （IGF-1水平，性激素水平和促性腺激素水平）在男性，这些更大 负性炎症效应有助于解释生长障碍的易感性增加 在男性中。这一假设是基于我们对从我们完成的研究中收集的数据的分析。 生长障碍性别差异的前瞻性多中心纵向研究 研究部分1）。我们的第1部分数据显示，随着骨龄的进展，标准化身高增加 在男性中更低。我们的第一部分研究结果表明，炎症对人的免疫系统产生更大的负面影响。 激素水平和男性的生长，并表明性别特异性分子途径导致 克罗恩病患儿的生长障碍。生长障碍的主要途径 在雄性中似乎是生长激素/IGF-1轴，在雄性中似乎是下丘脑/垂体/性腺轴。 在女性中。为克罗恩病儿童制定一种基于性别风险的治疗方法 疾病是必要的。然而，造成性别差异的具体分子机制， 生长障碍的特征仍然不明确。在此，我们建议扩大并继续 跟随我们的队列收集蛋白质组（目标1）和基因组（目标2）的信息，以提供 对生长障碍的新见解这些数据将增强我们确定 生长障碍性别差异的潜在机制（目的1和2），并发展 稳健的性别特异性预测模型，以识别高风险患者（目标3）。第二部分成长 研究将产生必要的数据，使我们能够开发一个高度需要的性别特异性 基于风险的小儿克罗恩病治疗方法，这将是一个主要的 临床实践的范式转变。建立适当的个性化的基于性别的风险 针对潜在炎症的药物治疗（因为改善生长的结果来自于 改善疾病控制）是至关重要的，因为只有非常窄的治疗间隔可用 在生长板关闭之前进行干预以促进生长。

Project Summary/Abstract Growth impairment is a common complication of pediatric Crohn’s disease. Normalization of growth is a marker of disease control and successful Crohn’s disease therapy. Treatment strategies for improving growth impairment and final adult height are currently suboptimal. The impact of Crohn’s disease on growth is potentially mediated by many factors, including inflammation, genetics, microbiome, nutrition, and medications. The continued presence of growth impairment primarily reflects continued suboptimal treatment of the underlying inflammation characteristic of Crohn’s disease. We hypothesize that the inflammation characteristic of Crohn’s disease has greater negative effects on endocrine growth regulators (IGF-1 levels, sex hormone levels, and gonadotropin levels) in males and that these greater negative inflammatory effects help to explain the increased susceptibility to growth impairment in males. This hypothesis is based on our analyses of data collected from our completed prospective multicenter longitudinal study of sex differences in growth impairment (Growth Study Part 1). Our Part 1 data show that as bone age progresses, standardized height gain is lower in males. Our Part 1 findings suggest inflammation exerts a greater negative effect on hormone levels and growth in males, and indicate that sex-specific molecular pathways lead to growth impairment in children with Crohn’s disease. The primary pathway to growth impairment appears be the growth hormone/IGF-1 axis in males and the hypothalamic/pituitary/gonadal axis in females. Developing a sex-specific risk-based treatment approach for children with Crohn’s disease is essential. However, the specific molecular mechanisms causing sex differences in growth impairment remain poorly characterized. Here, we propose to expand and continue to follow our cohort to harvest information on the proteome (Aim 1) and genome (Aim 2) to provide new insights into growth impairment. These data will enhance our ability to determine the underlying mechanisms of sex differences in growth impairment (Aims 1 and 2) and develop robust sex-specific predictive models to identify high-risk patients (Aim 3). Part 2 of the Growth Study will generate essential data that will enable us to develop a highly needed sex-specific risk- based pediatric Crohn’s disease treatment approach, which will represent a major paradigm shift in clinical practice. Institution of appropriate personalized sex-specific risk-based medical therapies targeting the underlying inflammation (since improved growth results from improved disease control) is essential since only a very narrow therapeutic interval is available to intervene to improve growth before growth plates close.