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

描述（由申请人提供）：间质性膀胱炎/膀胱疼痛综合征（IC/PBS）是一种慢性膀胱炎症，其特征是慢性盆腔疼痛、尿频和尿急，而这些症状没有其他明确的病因。IC/PBS是一种严重的疾病，可严重影响生活质量。由于IC/PBS的病因尚不清楚，目前的治疗在很大程度上是经验的，其疗效各不相同。为了改善病人的护理，迫切需要新的治疗方法。需要一个有效的动物模型来破译疾病的机制见解，以促进治疗发展。基于越来越多的证据支持至少一部分IC/PBS患者的炎症/自身免疫成分，我们开发了转基因膀胱炎模型（uroo - mcp -1和uroo - ova），以促进人类疾病的研究。urop -MCP-1模型通过尿路上皮分泌单核细胞趋化蛋白-1 (MCP-1)，模拟IC/PBS患者的超敏膀胱。相比之下，uroo -OVA模型在尿路上皮上表达一种膜形式的模型抗原卵清蛋白（OVA）作为自身抗原，并模拟某些IC/PBS患者的免疫/自身免疫性膀胱炎症。这两种模型代表了两种不同的致病途径（lps诱导的膀胱炎和自身免疫性膀胱炎）；然而，它们似乎具有共同的中枢炎症反应，并复制了IC/PBS患者的许多临床相关性。此外，这些模型对免疫调节剂有反应，为治疗发展提供了独特的潜力。本研究的基本目标是验证动物模型与未来临床试验的临床相关性。验证将根据临床发现在多个方面进行

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.