Research Description:

My lab is using a mutipronged approach to understand the cellular and molecular details of adult stem cell biology of the adult mammalian urinary bladder. The bladder is lined by a pseudo-stratified transitional urothelium continuously repopulated by an urothelial stem cell (USC). The rate of turnover of the cells in the normal transitional epithelium is slow but continuous: it takes more than 200 days for the progeny of a USC to mature and eventually be shed. Our studies show that following injury to the epithelium, the rate of differentiation and regeneration increases dramatically. To determine the dynamics of tissue regeneration in the adult bladder, we use a model of urothelial injury induced by infection with uropathogenic Escherichia coli (UPEC), the primary causative agent of a common infectious disease in women, urinary tract infections (UTIs). UPEC infection results in rapid sloughing of colonized terminally differentiated superficial cells, massive immune cell infiltration, and a remarkable spike in mitotic activity of the basal stem/progenitor cells such that the superficial layer is renewed within days.

Using a blend of confocal and electron microscopy, laser-capture, oligonucleotide, bioinformatics, histopathologic analyses, and inducible genetic disruption of key genes in mouse models, we are delineating the cellular mechanisms and molecular regulators that govern the normal rapid, injury-induced regenerative response of otherwise quiescent USCs and to apply what we learn about the normal mechanisms to shed light on the disease processes with abnormal urothelial turnover(e.g. recurrent UTIs, interstitial cystitis/painful bladder syndrome, bladder cancer). We have shown that a key molecular regulator of this process is the bone morphogenetic protein 4 (Bmp4) signaling pathway which is necessary for modulating the response to bacteria-induced epithelial injury by regulating USC niche activation. We are using transgenic and knock-out mice to assess how Bmp4 and other factors, such as sonic hedgehog, and wnt5a coordinate to regulate the complex epithelial developmental pathways that maintain the USC niche and its response to injury and disease. Our work encompasses studies of acute and recurrent UTIs to fundamental mechanisms of urinary bladder development and homeostasis, to bladder cancer biomarkers and finally to development of better strategies for treatment of recurrent UTIs.