Validation in Transgenic Animal Models of Clinical Correlates of IC/PBS

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DESCRIPTION (provided by applicant): Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic inflammatory condition of the urinary bladder characterized by symptoms of chronic pelvic pain and urinary frequency and urgency in the absence of other identified etiologies for these symptoms. IC/PBS is a significant disease and can severely affect quality of life. Since the etiology of IC/PBS remains unknown, current treatments are largely empirical and vary in their efficacy. To improve patient care, novel therapies are greatly needed. A valid animal model is required for deciphering the mechanistic insights of the disease for therapeutic development. Based on accumulating evidence supporting a component of inflammation/autoimmunity in at least a subset of IC/PBS patients, we have developed transgenic cystitis models (URO-MCP-1 and URO-OVA) to facilitate the studies of the human disease. The URO-MCP-1 model secretes monocyte chemotactic protein-1 (MCP-1) by the urothelium and mimics the hypersensitive bladders of IC/PBS patients. By contrast, the URO-OVA model expresses a membrane form of the model antigen ovalbumin (OVA) as a self-antigen on the urothelium and mimics immune/autoimmune bladder inflammation in certain IC/PBS patients. The two models represent two distinct pathogenic pathways (LPS-induced vs. autoimmune-based cystitis); however, they appear to share a common central inflammatory response and replicate many clinical correlates seen in IC/PBS patients. Moreover, these models are responsive to immunomodulatory agents, offering unique potential for therapeutic development. The fundamental goal of this study is to validate the clinical relevance of the animal models for futur clinical trials. The validation will be conducted in multiple aspects based on clinical findings in IC/PBS patients. These will include the hallmark symptoms of pelvic/bladder pain and urinary frequency and urgency, potential key biomarkers, and cortisol dysregulation (Aim 1). In addition, we will also develop mechanism-specific targeted therapy for bladder inflammation. Novel therapies consisting of both systemically and locally acting immunomodulatory agents (mNOX-E36 and RDP58) will be formulated for treating bladder inflammation in the animal models (Aim 2). It is our expectation that at the completion of this study we will have validated the relevance of the animal models and developed novel pharmacological therapies for bladder inflammation in these models. A valid animal model is critical for better understanding of the mechanisms behind IC/PBS and for developing effective interventions for this refractory human disease.