We have shown that the calcineurin pathway is activated following partial Bladder Outlet Obstruction (pBOO), and that inhibition with its known inhibitor cyclosporine A (CSA) results in a more favorable bladder phenotype. Despite the benefits that surgical models offer, they do have limitations: 1) there is a variable degree of hypertrophy. 2) Multiple pathways are simultaneously activated with pBOO. 3) Multiple cell types exist within the bladder wall in which the pathway may or not be activated. 4) There is a potential for changes induced by the pathway of interest in one cell population to induce changes in another. Despite their benefits in a recapitulation of the events that take place in clinical pBOO, the nature of surgical models makes the study of individual pathways and cell to cell interactions very difficult. In order to more fully investigate the mechanism(s) by which calcineurin mediates bladder wall hypertrophy, we now propose the development of a transgenic strategy that allows us to turn on calcineurin under the control of the doxycycline sensitive promoter within the urothelium or the smooth muscle cell populations. This will allow for a more precise mechanistic assessment of the role this pathway plays in bladder wall hypertrophy following pBOO. In addition the reagent mouse that we generate in this proposal will find applicability in the study of other systems (such as cardiac, pulmonary, vascular, and neural) where the calcineurin pathway is active.
Bladder wall hypertrophy often develops in patients either as a result of an anatomic blockage or as a result of abnormal voiding due to nerve injury as seen patients spina bifida or spinal cord injury. We have shown that the calcineurin pathway is activated following partial outlet obstruction in the mouse. This grant proposal seeks to develop a more refined proof of concept using modern transgenic strategies that calcineurin helps mediate bladder wall hypertrophy. This model offers us and improved platform in which to demonstrate the potential benefit of using cyclopsorine A (a known calcineurin inhibitor) as a treatment to preserve bladder function. A strategy of preserving function and preventing the end stage bladder using pharmacologic manipulation that is instituted early will offer these patients an improved quality of life.
