In the past 1 and 1/2 years, supported by grant 1 R55DK51374, we have modified and tested the feasibility of developing a reproducible rat model to study female stress urinary incontinence. We have studied the effect of pregnancy and delivery on the ultrastructure and function of the continence mechanism. We also modified our model by using pregnant rats and placed a intravaginal balloon under traction to direct the force to the levators and perineum to simulate the human situation. The information we have gained strongly support our opinion that the continence mechanism in the rats is similar to that of humans. We therefore propose to study the molecular mechanism involved in the pathogenesis of female stress urinary incontinence. We hypothesize that birth trauma, hormonal deficiency (menopause) and old age affect the gene and protein expression of several growth factors (IGF system, FGF, NGF, TGF, PDGF) and receptors (adrenergic, muscarinic and estrogen) which in turn change the structure and function of the continence mechanism. The hypothesis will be tested by completing the following specific aims: 1. To study and compare the functional, ultrastructural, cellular and molecular changes of the continence mechanism a). during pregnancy and after spontaneous delivery, b) after oxytocin-induced delivery and c) after delivery by cesarean section. 2. To examine the functional, ultrastructural, cellular and molecular changes of the continence mechanism after repeated birth trauma. 3. To examine the functional, ultrastructural, cellular and molecular changes of the continence mechanism after simulated birth trauma and bilateral ovariectomy. 4. To determine the functional, ultrastructural, cellular and molecular changes of the continence mechanism after combined simulated birth trauma, ovariectomy and aging.
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