Bladder cancer, urothelial development, urothelial regeneration, embryonic development, retinoic acid signaling, genetics of congenital abnormalities of the urinary tract.
My background is in developmental biology, examining the role of retinoids in different aspects of organogenesis. Several years ago my lab used mouse models to establish the sequence of events that occur during ureter maturation, a process where primitive ureters make direct connections with bladder, which when defective, is a common cause of urinary tract dysfunction. Mutants with abnormal Retinoic acid signaling develop massive bilateral hydronephrosis. Our studies suggest that these abnormalities are linked to defective apoptosis during ureter maturation, which normally depends on Casp-9. Our findings further suggest that Casp9 may be a direct transcriptional target of retinoids. We are currently part of a George O’Brien Urological Center, in collaboration with Jon Barasch and Ali Gharavi from the Dept. of Medicine. Our collective projects are focused on using mouse models to identify mutations that in humans, are linked to urinary tract abnormalities, including VUR and posterior urethral valves, a condition inherited by males that severely affects renal function about which little is understood. Most recently, my lab has focused on identification and characterization of progenitors that are important for development and regeneration of the urothelium, a water-proof barrier that lines the urinary outflow tract. The urothelium is also a source of epithelial cells that give rise to urothelial carcinoma. We find that retinoids are important for producing and regenerating superficial cells, a luminal population that is establishes and maintains the urothelial barrier. We find that Pparg, a transcription factor best known for it’s role in fat metabolism, is a likely downstream target of retinoids in the urothelium where Pparg plays an important role in development and regeneration, and acts as a modulator innate immunity in response to urinary tract infections. Pparg expression is down-regulated in the basal subtype of urothelial carcinoma, a lesion that displays squamous properties. Our studies with Pparg mutant mice suggest that Pparg may be normally be critical for preventing squamous differentiation and urothelial carcinoma.