Project 172595

Our research goal is to find new drug treatments for bladder obstruction. Obstruction creates multiple health problems including incontinence, recurrent urine infection, and kidney damage, resulting in nearly $30 billion in annual health care costs. Obstruction leads to pressure and distension injury, which is also accompanied by decreased oxygen delivery to the bladder muscle (hypoxia). The bladder muscle wall becomes thickened and fibrotic and eventually bladder function fails. We have developed an organ model which permits study of the rat bladder in culture. This organ culture system has shown that distension and hypoxia stimuli trigger specific enzymatic and molecular changes which drive smooth muscle overgrowth. Using computer analysis of the genes we have identified to date, expressed by the distended rat organ and by stretched human bladder muscle cells, we have found that the mammalian target of rapamycin (mTOR) and the epidermal growth factor receptor (EGFR) pathways may regulate bladder obstruction responses. We observe that the mTOR inhibitor drug rapamycin, is able to block growth of stretched cells and hypoxic cells. We have also reported that EGFR regulates BMSC growth triggered my stretching the organ in culture, and in cultured hypoxic BSMC. Therefore, we are testing the idea that hypoxia regulates muscle responses to distension using shared biological pathways. This project will exploit these two stimuli in our organ system to study 3 areas: 1. How hypoxia modifies distension responses in the bladder tissue using the mTOR & EGFR pathways, 2. How hypoxia modifies function of the component parts of the mTOR pathway in response to distension, and 3. Assessing rapamycin and the EGFR inhibitor Iressa to treat bladder damage in a live animal model of chronic bladder obstruction. These studies will provide significant new understanding and treatment directions for bladder obstruction.