A multi-omic investigation of uremic toxin sources and accumulation in children with kidney failure - PROJECT SUMMARY / ABSTRACT Children with kidney failure, either Chronic Kidney Disease Stage 5 requiring chronic dialysis (CKD5D) or acute kidney injury (AKI) requiring continuous veno-venous hemodiafiltration (CVVHDF) have high rates of morbidity and mortality. Complications are mediated by uremic toxins. All dialysis modalities have inherent efficacy limitations for removing various toxins. Understanding how toxins are derived and factors affecting their accumulation may identify novel targets for clinical intervention. The scientific goals are to: AIM 1 – characterize novel and known contributions of gut microbes to the biosynthetic pathways of selected uremic toxins using a multi-meta-omics approach, and AIM 2- identify differences in toxin accumulation and clearance between children with requiring CVVHDF vs children with CKD5D. The Paired pre/post-Dialysis Investigation of Global Metabolomics (P/paraDIGM) study is approved with existing study infrastructure and biobanked samples, which will support achievement of these AIMs. The candidate’s career development plan focuses on building three pillars of focus: PILLAR 1 - multi-omics science and technologies, PILLAR 2 – biostatistics, bioinformatics, and data science, PILLAR 3 – designing and conducting clinical trials. The candidate will develop these three pillars through a combination of experiential learning and structured coursework. The candidate will be guided by his primary mentor, Dr. Michelle Denburg, who has strong record mentoring junior investigators. The candidate will be advised by a committee with expertise in pediatric and adult nephrology, multi-omics, the gut microbiome, biostatistics, epidemiology, and computational biology. The candidate will transition from P/paraDIGM’s lead investigator to principal investigator. The candidate’s career goal is to become an independent translational multi-omics investigator with a program seeking to improve clinical monitoring and intervention on modifiable toxins in children with kidney failure. The K23’s research and career development advancement will support the candidate’s future R01 submission. The Children’s Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania (PennSOM) provide a strong institutional environment for carrying out the proposed research and career development plan. CHOP is one of the highest-volume pediatric dialysis centers in the country. CHOP and PennSOM host robust training programs to support junior faculty career development. CHOP and PennSOM are committed to protecting at least 80% of the candidate’s effort to support research and career development activities.
