The urinary outflow tract includes the Ureteropelvic junction, Straight Ureter, Trigone, Bladder and Urethra; structures critical for transport, storage and excretion of urine. Obstruction that blocks the flow of urine from the kidneys to the bladder, or reflux can result in hydronephrosis, a defect commonly detected in antenatal ultrasound that occurs in about 1% of the population. In the majority of individuals hydronephrosis will self- resolve without causing renal damage, however in a small number of cases hydronephrosis persists and can cause damage to the kidney and bladder. At present there is no way to distinguish between these outcomes. Identifying mutations that lead to VUR and obstruction will be important for diagnosis and clinical management of CAKUT, however understanding how and at which stages molecular pathways act will be essential for validation and interpretation of new findings from genetic studies.
In Aim 1, we will characterize the process of ureter maturation in the developing human urinary tract and we will generate a temporal and spatial Atlas of Gene expression. We will focus on genes that when mutated in mice or humans cause CAKUT in collaboration with the Gharavi Lab. These studies will be performed as part of the GUDMAP Consortium, and Aimed at producing an atlas of gene expression in the developing human urinary tract. The urinary outflow tract is lined with a specialized epithelium called the urothelium that maintains a waterproof and toxin resistant barrier that extends from the renal pelvis to the proximal urethra. The adult urothelium is one of the most quiescent epithelia in the body, but can rapidly regenerate in response to acute injury from Urinary tract infection (UTI) or exposure to toxins. However chronic injury caused by recurrent or persistent UTI, abnormal sensory nerve stimulation or chemicals can permanently damage the urothelium most likely due at least in part, to depletion of progenitor populations that normally produce superficial cells after injury. At present there is now way to repair or regenerate the damaged urothelium The studies proposed here will produce a molecular atlas of stromal/urothelial signaling pathways that are expressed during urothelial stratification and define urothelial sub-populations at functionally distinct sites in the developing human urinary tract. Understanding how urothelial cells are programmed and sustained, and how they regenerate will be important for generating sub-populations from IPS cells and will be critical for developing new strategies for treatment of patients with damaged bladders.
The urinary outflow tract is critical for urine transport, storage and excretion. The kidneys and ureters form independently of the bladder, but must connect during development to produce a patent outflow tract. Mistakes in this process are common, and can renal damage. The outflow tract is lined with the urothelium, waterproof epithelium that protects against pathogens and toxic substances. The urothelium can be damaged by chronic urinary tract infection or exposure to toxins, resulting in severe pain and voiding dysfunction for which at present there are no effective treatments. Generating an Atlas of gene expression and cell types in the human urothelium will be critical for developing strategies for urothelial regeneration and repair.
