Molecular events in urinary tract formation

Columbia University Health Sciences, New York NY

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Abstract

DESCRIPTION (provided by applicant): The urinary tract is composed of the kidneys, which filter blood and remove excess fluids, solutes and metabolic by-products from systemic circulation and an outflow tract that carries these wastes our of the body. The the ureters, bladder and urethra, form independently of the kidney connecting at midgestation to form a patent outflow tract. Ureter insertion, the connection process, involves a complex series of events, in which the ureter orifice moves from its original insertion site in the common nephric duct (CND), the most caudal Wolffian duct segment, to the urogenital sinus fusing with the primitive bladder epithelium. Defects in this process are associated with a wide spectrum of birth defects in humans affecting 1-2% of the population, including vesicoureteral reflux and obstruction that can damage the kidneys and cause end stage renal disease. We find that insertion of the ureter into the bladder depends on remodeling of the CND that enables to detach from its primary insertion site and move to the bladder epithelium, its final insertion site. Using mouse models, we have shown that ureter insertion depends on retinoic acid (RA) and that RA acts by inducing transcription of Ret, a gene that when mutated in humans causes renal malformations and vesico-ureteral reflux. Ret is likely to be important for CND remodeling however it is unclear which cellular processes it normally controls, and how RA controls Ret. This is an application for a Competitive Revision in which we propose to re-instate Aim 1 which was focused on understanding how RA and Ret control ureter inseriton into the research plan of the parent application "Molecular Events in Urinary Tract Formation". This Aim received an outstanding review but was dropped due to insufficient funding as we could not hire the necessary personnel to perform these studies. In addition to expanding the scope of our research, these requested funds will enable us to hire a full time GRA, Devangini Gandhi and retain a 1/2 time Post-doctoral, research scientist, Ian Chia, to carry out the work in Aim1, whom otherwise we would not be able to support. In additon, the inclusion of Ian Chia in this study will greatly enhance the speed by which the project can be completed which we expect to be within 2 years time. Thes proposed studies will lead to a deeper understanding the cellular and molecular interactions that are necessary for this ureter insertion, with the goal of elucidating the cause of obstruction in humans. PUBLIC HEALTH RELEVANCE: Urinary tract abnormalities are a common in humans, affecting 1-2% of the population and are a major cause of end stage kidney disease in children. Mutations in the RTK Ret, result in VUR both in humans and in mice. We find that retinoic acid is crucial for maintaining Ret expression in the LUT, and that loss of RA signaling leads to ureter insertion defects similar to those induced by Ret mutations.Understanding the normal mechanism by which RA and Ret regulate ureter insertion will lead to a deeper understand of the causes of LUT obstruction in humans.