Kids: Nocturnal Investigation into Glomerular Disease, Hypertension, and Transcriptomics (kNIGHT)

项目总结/摘要 患有蛋白尿性肾小球病的儿童患心血管疾病的风险相当大。除了有 在这一人群中，传统心血管疾病危险因素的患病率较高，超过一半的儿童 患有蛋白尿性肾小球病的患者经历夜间血压失调， 高血压或夜间血压下降减少（非下降模式）。夜间血压 在成人中，失调与不良心血管疾病结局独立相关。在这一背景下， 这项提案的目的是了解心血管疾病的风险，临床预测因素和分子生物学。 与蛋白尿性肾小球病儿童夜间血压失调相关的标志物 中心假设是，夜间血压失调独立与 蛋白尿性肾小球病患儿心血管靶器官损害随时间的进展是 进一步假设临床和分子标记物与夜间血压相关 失调表型本提案的具体目的是：（目的1）确定夜间血液 蛋白尿患儿血压失调与靶器官损害相关 肾小球疾病;（目的2）确定睡眠和昼夜节律相关的夜间血压预测因子 蛋白尿性肾小球疾病患儿的调节异常;（目的3）研究蛋白尿性肾小球疾病的分子通路、网络 与蛋白尿患儿夜间血压失调相关的代谢改变 使用多组学数据集成的肾小球病 .这项研究将调查夜间血压 一项对120名蛋白尿性肾小球病儿童进行的多中心纵向观察性研究中的调节异常 从肾病综合征研究网络（NEPTUNE）和治愈肾小球肾病网络入组 （CureGN）。心血管测量将随访三年，以确定夜间BP 失调表型与心血管靶器官损伤的进展相关。预测模型 然后将使用机器学习方法开发，以确定夜间血液的临床预测因素。 压力失调，特别强调睡眠和昼夜节律相关的预测因素。此外，A 将采用精确医学方法来确定夜间血压的分子标志物 使用多组学数据（基因组学、转录组学、蛋白质组学、代谢组学）整合的失调。本 最后，确定与夜间血液相关的健康风险、临床预测因子和分子标志物， 利用创新生物信息学研究蛋白尿性肾小球病患儿的压力失调 分析现有和新数据的方法将填补儿童人口的重大知识空白， 心血管风险很大。这项研究将最终指导预防和治疗，以有意义地改善 这些患有蛋白尿性肾小球病的儿童的心血管疾病结局。

PROJECT SUMMARY/ABSTRACT Children with proteinuric glomerulopathies are at considerable risk for cardiovascular disease. In addition to the high prevalence of traditional cardiovascular disease risk factors in this population, more than half of children with proteinuric glomerulopathies experience nocturnal blood pressure dysregulation, defined by nocturnal hypertension or a reduced decline in nocturnal blood pressure (non-dipping pattern). Nocturnal blood pressure dysregulation is independently associated with poor cardiovascular disease outcomes in adults. In this context, the objective of this proposal is to understand the cardiovascular disease risks, clinical predictors and molecular markers associated with nocturnal blood pressure dysregulation in children with proteinuric glomerulopathies. The central hypothesis is that nocturnal blood pressure dysregulation is independently associated with progression of cardiovascular target organ damage over time in children with proteinuric glomerulopathies. It is further hypothesized that clinical and molecular markers will be associated with the nocturnal blood pressure dysregulation phenotype. The specific aims of this proposal are: (Aim 1) To determine how nocturnal blood pressure dysregulation associates with target organ damage over time in children with proteinuric glomerulopathies; (Aim 2) To identify sleep- and circadian-related predictors of nocturnal blood pressure dysregulation in children with proteinuric glomerulopathies; (Aim 3) To investigate molecular pathways, networks and metabolic alterations associated with nocturnal blood pressure dysregulation in children with proteinuric glomerulopathies using multi-omic data integration . The proposed study will investigate nocturnal blood pressure dysregulation in a multi-center, longitudinal observational study of 120 children with proteinuric glomerulopathies enrolled from the Nephrotic Syndrome Study Network (NEPTUNE) and Cure Glomerulonephropathy Network (CureGN). Cardiovascular measures will be followed for three years to determine how the nocturnal BP dysregulation phenotype associates with progression of cardiovascular target organ damage. Predictive models will then be developed using machine learning methods to identify the clinical predictors of nocturnal blood pressure dysregulation, with a particular emphasis on sleep- and circadian-related predictors. Further, a precision medicine approach will be employed to define molecular markers of nocturnal blood pressure dysregulation using multi-omic data (genomics, transcriptomics, proteomics, metabolomics) integration. To this end, identifying the health risks, clinical predictors and molecular markers associated with nocturnal blood pressure dysregulation among children with proteinuric glomerulopathies using innovative bioinformatics approaches to analyze existing and novel data will fill a significant knowledge gap for a population of children at great cardiovascular risk. This study will ultimately guide prevention and treatment to meaningfully improve cardiovascular disease outcomes in these children with proteinuric glomerulopathies.