Novel Studies of Bladder Regeneration in a Rodent Model

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DESCRIPTION (provided by applicant): This application targets the millions of patients suffering from bladder disease/dysfunction related to congenital anomalies, cancer, infection, inflammation or lesions of the central or peripheral nervous system. Regardless of etiology, in all cases these conditions eventually result in largely irreparable damage to bladder tissue structure or function, ultimately affecting the ability of the bladder to fill, store or empty. The ensuing bladder dysfunction significantly reduces the patient's quality of life, and can also lead to significant morbidity due to upstream effects on the kidneys. Tissue engineering and regenerative medicine technologies represent a potential solution to the deficit of viable bladder tissue associated with these conditions. While the first clinical success of these techniques have recently been reported in young patients with congenital spinal cord lesions (i.e., myelomeningocele), there is no doubt that there is room for therapeutic improvement if one wishes to extend these technologies to the unmet medical needs of the much larger potential patient population. Because bladder regeneration in rodents and man shares several common features, we propose novel studies of bladder regeneration following subtotal cystectomy in a rodent model. The rationale is that improved mechanistic understanding of the normal bladder regeneration process in vivo would be an absolute prerequisite to further clinical progress. To this end we shall: Specific Aim #1: Assess progression of host tissue regeneration in vivo using micro CT and MRI imaging techniques and conscious cystometry measures. Specific Aim #2: Assess the progression of the host tissue regeneration response in vitro using pharmacological and physiological assays. Specific Aim #3: Characterize the cellular basis and histological features of the regenerative response of the urinary bladder. The combination of high resolution imaging modalities with direct measures of bladder function in vivo and tissue function and histology in vitro will establish the baseline characteristics of bladder regeneration as well as noninvasive markers for physiological milestones associated with normal bladder regeneration. The power of this approach stems from comparison of the regenerated bladder with the native bladder from the same animal. The over-ridding goal is to leverage the novel insights obtained to maximize the body's potential for achieving enhanced/maximal tissue formation in vivo. PUBLIC HEALTH RELEVANCE Cancer, congenital deformities, infection, inflammation, traumatic injury and nerve lesions produce irreversible damage to bladder tissue resulting in a permanent impairment in bladder function. Such debilitating impairments affect millions of Americans and lead to a poor quality of life. We propose to study the process of bladder regeneration in a clinically relevant rodent model in order to better apply tissue engineering and regenerative medicine technologies to the creation of new functional tissue derived from the patients own cells.