Research Project 1: A Multidimensional Molecular Atlas of Healthy and Diseased Human Pediatric Kidney

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Abstract/Project Summary Kidney disease is common and deadly with frequent onset in childhood. Kidney and urinary tract congenital anomalies account for the majority of renal failure in children. Glomerular diseases and acute kidney injury (AKI) occur in up to 60% of neonatal and pediatric intensive care patients, directly correlating with length of stay, subsequent disability, and mortality. Kidney insults in childhood including ischemia, hyperoxia, infection and nephrotoxic drug/environmental exposures impair glomerular, tubular and bladder physiologic maturation and function resulting in overt chronic renal disease (CKD), and with stealthier hypertension and proteinuria. Although molecular interrogation of fetal and adult kidney is advanced, data on the postnatal developing and injured pediatric kidney and urinary tract are lagging due to lack of pediatric samples of healthy / reference kidneys and a network for investigation. This dataset is critical to understand postnatal kidney disease in all living children and to augment investigation of various consortia interrogating molecular signatures from children with CKD. This pediatric kidney atlas project (pKidCAP) is a unique opportunity to unite a collaborative set of investigators together with a biomedical core (pKidBIO) with a proven source of donor pediatric organs to build an atlas across age, race and sex. The pKidCAP will apply snRNAseq/ATACseq for defining cell specific gene expression and cis-regulatory elements from the same cell. Cell type and state diversity will be mapped across the pediatric life cycle on tissue using near single cell spatial transcriptomics. These maps will be generated on healthy and a subset of pediatric kidney disease biopsies that can inform disease model studies in Project 2 and other consortia investigating similar diseases. Whole genome sequencing in all of the samples will provide a link of expression data associated with discrete regions on the active DNA site in single cells to resolve corresponding SNPs or deleterious variants to their cell identities. The pKidCAP atlas will serve as a benchmark for the research community interested in rebuilding kidneys, elucidating mechanisms of kidney maturation and homeostasis, and mapping GWAS traits to active states to support causality. Studies using animal models and organoids from iPS cells will use this dataset as a key reference to prioritize research for drug design relevant to pediatric kidney disease. The unique data and maps will attract expertise outside traditional kidney researchers, including computational biologists and informaticists to design better analytical tools and new methods of data mining for new discoveries by combining multimodal datasets across time points from pediatric to adult ages. Researchers in machine learning, ageing research and tissue engineering will be drawn to solve fundamental aspects of cellular differentiation in relation to disease, ageing and tissue engineering that could be broadly applicable to other organ systems. This project will also be a unique opportunity to attract students and trainees who are embarking on single cell multiomics projects, thereby increasing the future cohort of researchers in this field.