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 生长发育障碍是儿童克罗恩病的常见并发症。的正规化 生长发育是疾病控制和克罗恩病治疗成功的标志。治疗 改善生长发育障碍和最终成人身高的策略目前并不理想。这个 克罗恩病对生长的影响可能受到许多因素的影响，包括 炎症、遗传学、微生物组、营养学和药物。持续存在的 增长障碍主要反映了对潜在风险的持续次优处理 克隆氏病的特点是炎症。我们假设炎症 克罗恩病的特点对内分泌生长调节剂有较大的负面影响 (IGF-1水平、性激素水平和促性腺激素水平)，并且这些水平更高 负面炎症效应有助于解释生长障碍易感性增加的原因 在男性身上。这一假设是基于我们对从已完成的 生长发育障碍性别差异的前瞻性多中心纵向研究 研究(第一部分)。我们的第一部分数据显示，随着骨龄的增长，标准化的身高增长是 男性的比例较低。我们的第一部分研究结果表明，炎症对 激素水平和男性的生长，并表明性别特异性的分子途径导致 克罗恩病儿童的生长发育障碍。导致生长障碍的主要途径 男性的生长激素/IGF-1轴和下丘脑/垂体/性腺轴 在雌性身上。为克罗恩病儿童开发一种基于性别的风险治疗方法 疾病是必不可少的。然而，导致性别差异的特定分子机制 生长障碍的特征仍然很差。在这里，我们建议扩大并继续 跟随我们的队列收集关于蛋白质组(目标1)和基因组(目标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 性别差异在发育障碍中的潜在机制(目标1和2)和发展 用于识别高危患者的稳健的特定性别预测模型(目标3)。成长的第二部分 研究将产生重要的数据，使我们能够开发出迫切需要的特定性别 基于风险的儿科克罗恩病治疗方法，这将是一个主要的 临床实践中的范式转换。以风险为基础的适当个性化的性别机构 针对潜在炎症的药物治疗(因为生长的改善源于 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 在增长板块关闭之前进行干预以改善增长。