The aim of this research originally examined the mechanisms by which urothelial apical membranes maintain large chemical gradients. More recently it was shifted to studies of mechanisms by which urothelium sustains and recovers from injury. We have examined several injury models, including an allergic model in guinea pigs, feline interstitial cystitis, and models of injury involving radiation, carcinogenesis in response to the alkylating agent, MNU, and direct urothelial injury due to protamine. The newest initiatives involve utilizing transgenic and conditional bladder knockouts in mice to investigate molecular pathways which may be involved in cancer and interstitial cystitis/painful bladder syndrome. These projects involve close collaboration with the group of Dr. Raghu Kalluri, head of the Division of Matrix Biology at BIDMC.
Failure of urothelial barrier results in chemical and infectious cystitis, and is thought to be important in the etiology of interstitial cystitis (IC) and potentially cancer. Therefore, defining how superficial urothelial cells (umbrella cells) differentiate and maintain a barrier apical membrane will provide insights into a number of diseases where epithelial integrity is compromised. Epithelial repair following damage requires three functional changes in the epithelial cells themselves: spreading, migration, and proliferation. Each of these processes normally requires the participation of integrins. Therefore we are developing a bladder-specific integrin knockout mouse to explore the role of these cell and matrix adhesion molecules in bladder integrity and repair.