Sex Differences in Statural Growth Impairment in Pediatric Crohn's Disease

儿童克罗恩病身高发育障碍的性别差异

• 批准号: 8632686
• 负责人: Neera Gupta
• 金额: $ 64.7万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8632686
• 关键词: Adolescent; Adult; Adverse effects; Age; Albumins; Androgens; Area; Biological Markers; C-reactive protein; Characteristics; Child; Childhood; Chronic; Chronic Childhood Arthritis; Clinical; Cohort Studies; Complication; Crohn' s disease; Cross-Sectional Studies; Cystic Fibrosis; Data; Endocrine; Erythrocyte Sedimentation Rate; Estradiol; Etiology; Female; Follicle Stimulating Hormone; Gonadal Steroid Hormones; Gonadotropins; Growth; Health; Height; Hormones; Impairment; Inflammation; Inflammatory; Inflammatory disease of the intestine; Insulin-Like Growth Factor I; Interleukin-6; Intestines; Longitudinal Studies; Luteinizing Hormone; Measures; Mediating; Mediator of activation protein; Medical; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Physicians; Predisposition; Rattus; Refractory; Reporting; Research; Research Design; Risk; Role; Serum; Severity of illness; Sex Characteristics; Somatotropin; Staging; Symptoms; Systemic Lupus Erythematosus; Testing; Testosterone; Therapeutic; Tumor Necrosis Factor-alpha; Urine; Work; base; bone age; cytokine; high risk; human TNF protein; hypothalamic pituitary gonadal axis; improved; in vitro Model; inflammatory marker; innovation; male; nutrition; predictive modeling; primary outcome; prospective; sex; treatment strategy; urinary

DESCRIPTION (provided by applicant): Statural growth is a dynamic marker of overall health in pediatric patients. Statural growth impairment is a common complication of pediatric Crohn's disease. 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, nutrition, and medications. One potential avenue for understanding the pathogenesis of impaired growth in Crohn's disease is that it is more common in males. Since insulin-like growth factor-1 (IGF-1) is the primary mediator of growth hormone's (GH) effects on statural growth, and since sex steroids have a direct effect on the pubertal growth spurt, we hypothesize that the inflammation characteristic of Crohn's disease has greater adverse effects on endocrine growth regulators (IGF-1 levels, sex hormone levels, and gonadotropin levels) in males and that these greater negative inflammatory effects help explain the increased susceptibility to growth impairment in males. This hypothesis is based on our analyses of cross-sectional data collected prospectively in 82 patients showing that standardized IGF-1 levels were lower in males and that inflammatory markers were associated with sex hormone and gonadotropin levels in males, not females. These data suggest that the impact of disease severity (inflammation) on growth differs by sex. Here, we propose to extend these findings by conducting a prospective multicenter longitudinal cohort study of 125 pediatric patients with Crohn's disease (bone age 9-12 years in females and 10-14 years in males) who will be followed for 2 years. In Aim 1, we will determine the role of hormones in sex-specific growth impairment in Crohn's disease. In Aim 2, we will determine the impact of inflammation, measured by inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-1RA) and non-specific inflammatory markers (ESR, CRP, albumin), on hormones (IGF-1, sex hormones, gonadotropins) and sex- specific growth impairment in Crohn's disease. In Aim 3, we will develop a predictive model for each sex to identify patients with Crohn's disease at high risk for developing growth impairment refractory to standard therapeutic approaches based on a panel of serum and urine biomarkers and clinical variables. The research proposed here is innovative because it offers a new area of focus: the impact of inflammation on the hypothalamic-pituitary-gonadal axis in addition to the GH-IGF-1 axis and the impact of these pathways on height velocity. Furthermore, we will identify patients at high risk for developing growth impairment refractory to standard therapeutic approaches. Understanding the underlying mechanisms of sex differences in growth impairment in Crohn's disease may help us to develop new targeted medical treatment strategies to improve height velocity and final adult height and to optimize current treatments in high-risk patients. These high risk patients may benefit from early introduction of high level medications ("top-down" approach), a treatment paradigm that would be a major turning point in pediatric Crohn's disease therapy.

描述（由适用提供）：状态增长是小儿患者总体健康的动态标志。状态生长障碍是小儿克罗恩病的常见并发症。目前，改善生长障碍和最终成人身高的治疗策略目前是最佳的。克罗恩病对生长的影响可能是由许多因素（包括感染，营养和药物）介导的。了解克罗恩病增长受损的发病机理的一个潜在途径是，它在男性中更为常见。 Since insulin-like growth factor-1 (IGF-1) is the primary mediator of growth horsene's (GH) effects on status growth, and since sex stereoids have a direct effect on the pubertal growth spurt, we hypothesize that the inflammation characteristic of Crohn's disease has greater adverse effects on endocrine growth regulators (IGF-1 levels, sex horsenes levels, and gonadotropin levels) in males and that these greater negative炎症作用有助于解释男性对生长障碍的敏感性增加。该假设是基于我们对82例患者的前瞻性横截面数据的分析，表明男性标准化的IGF-1水平较低，并且炎症标志物与男性，女性而非女性的性激素和性激素和促性腺激素水平有关。这些数据表明，在AIM 1中，我们将确定恐怖症在特定于性别的生长障碍中的作用在克罗恩病中。在AIM 2中，我们将确定125例克罗恩病儿科患者的影响（女性为9-12岁，男性为10-14岁），这些患者将受到2年的追踪。在AIM 1中，我们将确定恐怖症在特异性增长障碍中在克罗恩病中的作用。在AIM 2中，我们将确定AIM 3的影响，我们将为每个性别开发一个预测模型，以鉴定克罗恩病患者具有高风险的患者，该患者会根据血清和尿液生物标志物和临床变量的小组对标准治疗方法产生对标准治疗方法的难治性。此处提出的研究具有创新性，因为它提供了一个新的重点领域：除了GH-IGF-1轴以及这些途径对高度速度的影响之外，感染对下丘脑 - 垂体 - 基达轴的影响。此外，我们将确定患者对标准治疗方法的难治性的高风险患者。了解克罗恩病增长障碍性别差异的潜在机制可能有助于我们制定新的有针对性的医疗治疗策略，以提高身高速度和最终的成人身高，并优化高风险患者的当前治疗方法。这些高风险患者可能会从早期引入高水平药物（“自上而下”方法）中受益，这将是小儿克罗恩病治疗的主要转折点。