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

儿童克罗恩病身高发育障碍的性别差异：第 2 部分

• 批准号: 10638422
• 负责人: Neera Gupta
• 金额: $ 73.26万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-11 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10638422
• 关键词: Adult; Age; Anti-Inflammatory Agents; Biological; Biological Markers; Characteristics; Child; Childhood; Chronology; Clinical; Complication; Crohn' s disease; Data; Data Analyses; Data Set; Disease Marker; Endocrine; Epiphysial cartilage; Etiology; Female; Genetic; Genome; Genotype; Gonadal Steroid Hormones; Gonadotropins; Growth; Harvest; Height; Hormones; IL8 gene; Impairment; Inflammation; Inflammatory; Institution; Insulin-Like Growth Factor I; Interferon Type II; Interleukin-6; Investigation; Lead; Longitudinal Studies; Mediating; Medical; Modeling; Molecular; Pathogenesis; Pathway interactions; Patient risk; Patients; Pediatric Crohn' s disease; Pharmaceutical Preparations; Phenotype; Predisposition; Proteins; Proteome; Proteomics; Publishing; Refractory; Risk; Serum; Sex Differences; Somatotropin; Standardization; Testing; Therapeutic; bone age; clinical practice; cohort; cytokine; differential expression; disorder control; genome wide association study; genome-wide; high risk; hypothalamic pituitary gonadal axis; improved; insight; male; microbiome; nutrition; polygenic risk score; predictive modeling; prospective; response; risk stratification; sex; targeted treatment; theories; trait; treatment strategy

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.

项目摘要/摘要 生长障碍是小儿克罗恩病的常见并发症。归一化 生长是疾病控制和成功克罗恩病疗法的标志。治疗 目前，改善生长障碍和最终成人身高的策略目前是最佳的。这 克罗恩病对生长的影响可能是由许多因素介导的，包括 炎症，遗传学，微生物组，营养和药物。持续存在 生长障碍主要反映了基础的持续次优治疗 克罗恩病的炎症特征。我们假设炎症 克罗恩病的特征对内分泌生长调节剂具有更大的负面影响 （IGF-1水平，性激素水平和促性腺激素水平）在男性中，并且这些更大 负炎症作用有助于解释增强生长障碍的敏感性 在男性中。该假设基于我们从完成的数据分析 预期的多中心纵向研究生长障碍的性别差异（增长） 研究第1部分）。我们的第1部分数据显示，随着骨骼年龄的进展，标准化的高度增益为 男性较低。我们的第1部分的调查结果表明，注射对 雄性的马龙水平和生长，表明性别特异性的分子途径导致 克罗恩病儿童的生长障碍。生长障碍的主要途径 似乎是男性和下丘脑/垂体/性腺轴的生长骑马/IGF-1轴 在女性中。为克罗恩的儿童开发针对特定性风险的治疗方法 疾病是必不可少的。但是，特定的分子机制导致性别差异 生长障碍的特征仍然很差。在这里，我们建议扩展并继续 遵循我们的队列以收获有关蛋白质组（AIM 1）和基因组（AIM 2）的信息，以提供 对增长障碍的新见解。这些数据将增强我们确定的能力 性别障碍中性别差异的潜在机制（目标1和2）并发展 稳健的性别特异性预测模型以识别高危患者（AIM 3）。增长的第2部分 研究将产生基本数据，这将使我们能够开发出急需的性别特定性 基于风险的小儿克罗恩病治疗方法，这将代表主要 临床实践中的范式转移。适当的个性化性别特定风险的制度 针对潜在影响的医疗疗法（因为 改善疾病控制）至关重要，因为只有非常狭窄的治疗间隔 干预以改善生长板之前的生长。