Severe bladder pathology often occurs following bladder neck obstruction and can lead to renal damage. It is well established that a prolonged obstruction tot urine flow leads to an increase in bladder mass. The cell-to-cell interactions and the role of growth factors in governing the growth and differentiation of normal bladder smooth muscle cells (SMC) and the response to bladder obstruction remains unclear. We will test the hypothesis that bladder obstruction leads to hypertrophy/hyperplasia, in part mediated by the growth factors/modulators Insulin Like Growth Factor- 1 (igf-1) and Parathyroid Hormone-related Protein (PTHrP). We will create and characterize a model of bladder outlet obstruction in the mouse to enable transgenic approaches to be used to elucidate the roles of IGF-1 and PTHrP.
Five specific aims will be utilized to: 1. Develop and characterize a mouse model of bladder outlet obstruction with no respect to cystometric and morphologic changes. 2. Determine the effect of acute (0-14 days) chronic (4-6 weeks) outlet obstruction on the expression of SMC-specific markers in bladder. 3. Determine the effect of reversal of outlet obstruction at as early (7 days) or late (4 weeks) time-points on cystometry, morphology and SMC markers. 4. Evaluate the role of IGF-1 in bladder differentiation by characterizing the bladder in terms of cystometry, morphology and SMC markers in transgenic mice over-expressing IGF-1 (which show increased bladder mass), or its binding protein IGFBP-4, and determine the effect of outlet obstruction in these animals. 5. Evaluate the role of PTHrP in regulating bladder growth and differentiation by characterizing the bladder cognitive receptor, and determine the effect of outlet obstruction in these animals. We expect to define the time-course of bladder remodeling by this approach and elucidate the role of growth factors/modulators in the underlying mechanisms of bladder hypertrophy and hyperplasia. Identifying which factor or combination of factors can reverse the damage caused by bladder hypertrophy could enable normal bladder SMC development to occur and lead to the future development of novel therapeutic strategies.
| Szucsik, John C; Lewis, Alfor G; Marmer, Daniel J et al. (2004) Urogenital tract expression of enhanced green fluorescent protein in transgenic mice driven by a smooth muscle gamma-actin promoter. J Urol 171:944-9 |
