Integrative Molecular Epidemiology Approach to Identify Nephrotic Syndrome Subgroups

摘要

ABSTRACT Although patients with Nephrotic Syndrome (NS) present with shared clinical signs and symptoms (proteinuria, hypoalbuminemia, hyperlipidemia and edema), there is dramatic variability in prognosis and response to therapy, frustrating patients, families and their clinicians. Even within the histopathologic categories used in the current diagnostic approach (e.g. minimal change disease, focal segmental glomerulosclerosis), there is dramatic variability in disease progression and response to therapy, highlighting the underlying biological heterogeneity within the groups. Small studies with broad, clinical patient inclusion criteria have demonstrated that a subset of patients respond well to anti-TNF therapy, but accurate pre-treatment response of those individuals is not possible based on routine clinical parameters. This project will leverage the Nephrotic Syndrome Study Network (NEPTUNE) cohort study, a multi-center prospective study of 600 patients with FSGS, MCD and MN with rich clinical data, kidney biopsy tissue and gene expression profiles. This study will leverage the kidney tissue gene expression data to identify a subgroup of patients with TNF-alpha pathway activation, assess associated clinical outcomes and identify non- molecular predictors of the subgroup. The aims are: Aim 1: To identify a subgroup of Nephrotic Syndrome patients with homogeneous activation of the TNF-alpha transcriptional pathway. Aim 2: To compare molecular subgroups with conventional clinical-pathologic classification in clinical outcome prediction. Aim 3: To identify non-invasive markers (e.g. demographics, blood and urine markers), standard pathology features and novel pathologic biopsy descriptors associated with the TNF-alpha subgroup. To accomplish this project, the applicant will pursue formal training in systems biology, genetic epidemiology and bioinformatics. She will be mentored by a multi-disciplinary team with expertise in systems biology, epidemiology and bioinformatics. The long term objective is to improve the clinical care of patients with Nephrotic Syndrome by improved understanding of the underlying biology, identifying novel biomarkers and potential therapeutic targets for future validation in animal models and mechanistic-based interventional clinical trials.