Congenital Anomalies of the Kidney and the Urinary Tract (CAKUT) account for a large fraction of congenital malformations and are associated with significant morbidity and mortality in children and young adults. In the previous funding cycle, we have successfully applied genome-wide association study (GWAS), exome sequencing, and copy-number variant (CNV) analysis to identify novel genes and loci for different CAKUT subtypes. These recent findings demonstrate the effectiveness of using genetic approaches to refine clinical diagnoses and determine the pathogenesis of CAKUT subtypes, specifically vesicoureteral reflux (VUR) and its complications. Based on this data and the declining cost of sequencing, which allows for genetic testing to be increasingly incorporated into clinical care, we aim to explore the potential of genetic testing in Urology. To aid in this endeavor, we have developed a curated list of genes involved in lower urinary tract defects and determined the frequency of rare variants in these genes in healthy populations. In this application for Project 1 of the Columbia George M. O?Brien Urology Research Center we will determine the diagnostic utility of exome sequencing for clinical care in patients with simple Urinary Tract Infections (UTIs) and those with lower urinary tract defects with and without UTIs. We will also identify new genes contributing to VUR and UTI by case- control exome-wide association study. Additionally, in collaboration with the Microbial Genomics Biomedical Core, we will examine genotype-phenotype correlations, including analysis of the urinary microbiome in patients with different mutations and structural defects. Furthermore, we will perform rare variant burden tests to identify new genes predisposing to UTI and VUR, and examine the implication of these genetic discoveries to detect novel additional clinical associations with PheWAS and microbiome analysis based on genotype data. With these aims, we will fulfill the larger mission of the Columbia O?Brien Center by investigating the genetic, cellular and metabolic basis of UTI as well provide new insight into the pathogenesis of disorders highly relevant to the field of benign urology while facilitating the introduction of Precision Medicine into the practice of Pediatric Urology.
| Wang, Xueqiao; Zheng, Xiaoqing; Zhang, Juanlian et al. (2018) Physiological functions of ferroportin in the regulation of renal iron recycling and ischemic acute kidney injury. Am J Physiol Renal Physiol 315:F1042-F1057 |
| Sanna-Cherchi, Simone; Westland, Rik; Ghiggeri, Gian Marco et al. (2018) Genetic basis of human congenital anomalies of the kidney and urinary tract. J Clin Invest 128:4-15 |
| Joseph, Diya B; Chandrashekar, Anoop S; Abler, Lisa L et al. (2018) In vivo replacement of damaged bladder urothelium by Wolffian duct epithelial cells. Proc Natl Acad Sci U S A 115:8394-8399 |
| Kiryluk, Krzysztof; Bomback, Andrew S; Cheng, Yim-Ling et al. (2018) Precision Medicine for Acute Kidney Injury (AKI): Redefining AKI by Agnostic Kidney Tissue Interrogation and Genetics. Semin Nephrol 38:40-51 |
| Park, Jihwan; Shrestha, Rojesh; Qiu, Chengxiang et al. (2018) Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease. Science 360:758-763 |
| Sanna-Cherchi, Simone; Khan, Kamal; Westland, Rik et al. (2017) Exome-wide Association Study Identifies GREB1L Mutations in Congenital Kidney Malformations. Am J Hum Genet 101:789-802 |
| Costanzo, Maria Rosa; Ronco, Claudio; Abraham, William T et al. (2017) Extracorporeal Ultrafiltration for Fluid Overload in Heart Failure: Current Status and Prospects for Further Research. J Am Coll Cardiol 69:2428-2445 |
| Lopez-Rivera, Esther; Liu, Yangfan P; Verbitsky, Miguel et al. (2017) Genetic Drivers of Kidney Defects in the DiGeorge Syndrome. N Engl J Med 376:742-754 |
| Verbitsky, Miguel; Kogon, Amy J; Matheson, Matthew et al. (2017) Genomic Disorders and Neurocognitive Impairment in Pediatric CKD. J Am Soc Nephrol 28:2303-2309 |
| Werth, Max; Schmidt-Ott, Kai M; Leete, Thomas et al. (2017) Transcription factor TFCP2L1 patterns cells in the mouse kidney collecting ducts. Elife 6: |
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