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.