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

IC/PBS 临床相关性在转基因动物模型中的验证

• 批准号: 8626530
• 负责人: YI LUO
• 金额: $ 37.4万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-27 至 2016-09-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8626530
• 关键词: Affect; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Autoantigens; Autoimmune Process; Autoimmunity; Basic Science; Biological Markers; Bladder; Bladder Dysfunction; Cell Count; Chronic; Clinical; Clinical Research; Clinical Trials; Complex; Cystitis; Data; Dimethyl Sulfoxide; Disease; Etiology; Evaluation; Exhibits; Functional disorder; Future; Genitourinary system; Goals; Healthcare Systems; Histopathology; Human; Hydrocortisone; Hypersensitivity; Immune; Increased frequency of micturition; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Interstitial Cystitis; Investigation; Lead; Lipopolysaccharides; Mediating; Membrane; Modeling; Monocyte Chemoattractant Protein-1; Nerve Growth Factors; Neurogenic Inflammation; Ovalbumin; Pain; Pain Research; Pathway interactions; Patient Care; Patients; Pelvis; Peptides; Peripheral Blood Mononuclear Cell; Production; Property; Prophylactic treatment; Quality of life; RDP58; Refractory; Research; Role; Serum; Staging; Stimulus; Substance P; Symptoms; T-Lymphocyte; Testing; Therapeutic; Toxin; Transgenic Animals; Transgenic Organisms; Tumor Necrosis Factor-alpha; Urine; Urothelium; Validation; Variant; base; bladder pain; chemokine; chronic pelvic pain; clinically relevant; cytokine; effective intervention; expectation; human disease; hypothalamic-pituitary-adrenal axis; improved; indexing; insight; interdisciplinary approach; intravesical; mast cell; micturition urgency; novel; novel therapeutics; public health relevance; therapeutic development; translational study; urinary

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.

描述（由申请方提供）：间质性膀胱炎/膀胱疼痛综合征（IC/PBS）是一种膀胱慢性炎症性疾病，其特征为慢性盆腔疼痛、尿频和尿急症状，这些症状无其他确定的病因。IC/PBS是一种严重的疾病，可严重影响生活质量。由于IC/PBS的病因仍然未知，目前的治疗主要是经验性的，其疗效各不相同。为了改善患者护理，非常需要新的治疗方法。需要一个有效的动物模型来解释疾病的机制见解，以用于治疗开发。基于支持至少一部分IC/PBS患者中炎症/自身免疫组分的累积证据，我们开发了转基因膀胱炎模型（URO-MCP-1和URO-OVA），以促进人类疾病的研究。URO-MCP-1模型通过尿道分泌单核细胞趋化蛋白-1（MCP-1），并模拟IC/PBS患者的过敏性膀胱。相比之下，URO-OVA模型表达膜形式的模型抗原卵清蛋白（OVA）作为尿道上的自身抗原，并模拟某些IC/PBS患者中的免疫/自身免疫膀胱炎症。这两种模型代表了两种不同的致病途径（LPS诱导的与基于自身免疫的膀胱炎）;然而，它们似乎具有共同的中枢炎症反应，并复制了IC/PBS患者中观察到的许多临床相关性。此外，这些模型对免疫调节剂有反应，为治疗开发提供了独特的潜力。本研究的基本目的是验证动物模型的临床相关性，以供将来的临床试验。将根据以下临床结果从多个方面进行验证： IC/PBS患者。这些将包括骨盆/膀胱疼痛和尿频尿急的标志性症状，潜在的关键生物标志物和皮质醇失调（目标1）。此外，我们还将开发针对膀胱炎症的机制特异性靶向治疗。将配制由全身和局部作用的免疫调节剂（mNOX-E36和RDP 58）组成的新型疗法用于治疗动物模型中的膀胱炎症（目的2）。我们期望在完成本研究时，我们将验证 的动物模型，并开发了新的药物治疗膀胱炎症在这些模型。有效的动物模型对于更好地理解IC/PBS背后的机制以及开发针对这种难治性人类疾病的有效干预措施至关重要。