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

儿童：肾小球疾病、高血压和转录组学的夜间调查 (kNIGHT)

基本信息

批准号：
10583680
负责人：
Christine B Sethna
金额：
$ 74.68万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-15 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583680
关键词：
Adult Age Ambulatory Blood Pressure Monitoring American Heart Association Atherosclerosis Bioinformatics Blood Pressure Cardiac Cardiovascular Diseases Cardiovascular system Child Child Health Chronic Kidney Failure Clinical Data Clinical Markers Data Development Disease Disease Marker Disease Outcome Dyslipidemias Echocardiography Enrollment Functional disorder Funding Future Gene Expression Genes Genomics Goals Guide prevention Health High Prevalence Home Hour Hydrocortisone Hypertension Inflammation Intake Investigation Kidney Knowledge Laboratories Left Left Ventricular Dysfunction Left Ventricular Hypertrophy Left Ventricular Mass Link Lipids Longitudinal Studies Longitudinal, observational study Machine Learning Measurement Measures Metabolic Methodology Molecular Morbidity - disease rate Multiomic Data Nephrotic Syndrome Nocturnal Hypertension Organ Outcome Pathologic Pathway interactions Patients Pattern Phenotype Physical activity Physiologic pulse Population Prevention Proteomics Questionnaires Rare Diseases Renal glomerular disease Research Risk Risk Factors Risk Marker Risk Reduction Salivary Sleep Sleep Apnea Syndromes Sodium Systems Biology Time United States National Institutes of Health Validation Ventricular Whole Blood Work actigraphy arterial stiffness cardiovascular disorder risk cardiovascular health cardiovascular risk factor circadian clinical predictors cohort data integration design differential expression experience fatty acid metabolism high risk high risk population improved indexing innovation machine learning method metabolomics molecular marker mortality novel observational cohort study patient oriented precision medicine predictive marker predictive modeling randomized, clinical trials sleep quality transcriptome transcriptomics

项目摘要

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.

项目概要/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。除了该人群中传统心血管疾病危险因素患病率高，超过一半为儿童患有蛋白尿性肾小球病的人会经历夜间血压失调，定义为夜间血压高血压或夜间血压下降减少（非下降模式）。夜间血压调节失调与成人心血管疾病的不良结局独立相关。在此背景下，该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水平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与蛋白尿性肾小球病儿童心血管靶器官损伤随时间的进展。这是进一步假设临床和分子标志物与夜间血压有关失调表型。该提案的具体目标是：（目标 1）确定夜间血液如何随着时间的推移，蛋白尿儿童的压力失调与靶器官损伤相关肾小球病; （目标 2）确定夜间血压的睡眠和昼夜节律相关预测因素患有蛋白尿性肾小球病的儿童的失调；（目标 3）研究分子途径、网络蛋白尿儿童夜间血压失调相关的代谢变化使用多组学数据整合的肾小球疾病。拟议的研究将调查夜间血压一项针对 120 名蛋白尿性肾小球病儿童的多中心纵向观察研究中的失调已加入肾病综合征研究网络 (NEPTUNE) 和治愈肾小球肾病网络（治愈GN）。心血管测量将进行三年，以确定夜间血压如何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来开发，以识别夜间血液的临床预测因素压力失调，特别强调与睡眠和昼夜节律相关的预测因素。进一步地，一个将采用精准医学方法来定义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）整合来调节失调。对此最后，确定与夜间血液相关的健康风险、临床预测因子和分子标记使用创新生物信息学研究蛋白尿性肾小球病儿童的压力失调分析现有数据和新数据的方法将填补儿童群体的重大知识空白极大的心血管风险。这项研究最终将指导预防和治疗，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。