Pediatric Kidney Single Cell Atlas Project

点击翻译按钮获取中文摘要

Abstract/Project Summary Kidney disease is common and deadly with frequent onset in childhood. Kidney and urinary tract congenital anomalies account for most of the renal failure in children while, in addition, secondary acute kidney injury (AKI) occurs in up to 60% of neonatal and pediatric intensive care patients, directly correlating with length of stay, subsequent disability, and with early mortality. Kidney insults in childhood including ischemia, hyperoxia, infection and nephrotoxic drug/environmental exposures impair kidney maturation and function resulting in chronic renal disease (CKD) and with stealthier hypertension, renal stones and proteinuria. The development of effective interventions and methods of early detection and severity measurements of renal disease in children is lagging in part due to a lack of knowledge of physiological and pathological changes that occur as the kidney matures. Molecular blueprints would dramatically enhance our ability to design effective approaches to intervene and prevent kidney dysfunction. This goal cannot be met, however, without having a source of pediatric kidney tissue to begin molecular interrogations to identify the uniquely human and developmental, ’omic instructions required to make and maintain healthy kidneys. The objective of the Washington University Kidney Single Cell Atlas Project (pKidCAP) is to create a highly unique and innovative Pediatric Center of Excellence that delivers novel concepts, knowledge and resources by providing spatially resolved single cell molecular maps of pediatric reference and diseased kidneys at several time points across the pediatric lifespan. The pKidCAP investigators will apply paired snRNAseq, snATACseq technologies for decoding gene regulation and expression from the same cell and use spatial transcriptomics to resolve the cellular diversity with morphology using healthy and disease samples from pediatric kidneys procured from the Biomedical core and in mouse model of glomerular disease. The educational and opportunity pool programs will promote enthusiasm and progress in pediatric kidney disease research by 1) providing human age-specific references for fetal and childhood kidney disease tissues, 2) enabling studies aimed to delineate cellular, morphological, physiological and molecular changes associated with postnatal kidney maturation, 3) accelerating scientific research aimed at ex vivo human kidney organoids, 4) establishing protocols for isolating differentiated kidney cell types at stages consistent with those seen in kidney tissue samples, 5) advancing drug toxicity screening, and by 6) designing validation studies of gene function and kidney engineering. The availability of the tissue and the outstanding data generated from them will attract new expertise outside kidney research developing spatial imaging and analytical technologies and research interested in physiological aging across the lifespan.