Inhibition of TLR4 for Treatment of Cystitis Pain

项目摘要 间质性膀胱炎/膀胱疼痛综合征（IC/BPS）是一种慢性和使人衰弱的炎症性疾病， 膀胱的特点是盆腔疼痛的标志性症状，在没有其他确定的 症状的病因。IC/BPS患者还经常具有排尿功能障碍，例如尿失禁增加。 频率和紧迫性。这种泌尿系统疾病是重要的，严重影响生活质量。其财务 美国医疗保健系统的负担是巨大的。由于IC/BPS的病因仍然难以捉摸，目前 治疗主要是经验性的，常常不令人满意，而且疗效各不相同。因此，努力开发新的 IC/BPS的治疗非常需要。先前的研究表明，改变Toll样受体（TLR）4 激活可能显著促进慢性疼痛患者疼痛加剧状态的启动和维持。 疼痛状况。TLR 4在许多细胞类型中表达，包括神经元和非神经元细胞。 中枢神经系统以及免疫细胞（例如单核细胞/巨噬细胞）和其它体细胞（例如， 膀胱上皮细胞）。一旦被激活，TLR 4介导促炎细胞因子的产生， 导致增强的中枢和外周免疫信号传导和随后的过度伤害感受 传输虽然TLR 4抑制对慢性疼痛缓解的作用已经在多个实验中得到证实， 动物模型（例如炎症性和神经性疼痛），这尚未在膀胱炎疼痛中进行研究， IC/BPS患者。最近，我们确定了改变TLR 4/TLR 2激活在IC/BPS中的主要作用。特别地， 我们观察到外周血中TLR 4介导的促炎细胞因子的产生增加， 单核细胞与更大的疼痛严重程度和共病疼痛的程度显著相关， IC/BPS患者。与我们的临床研究结果一致，我们发现膀胱炎疼痛与升高的 我们的临床前验证的转基因IC/BPS样中的全身和中枢TLR 4/TLR 2炎症反应 动物模型（URO-OVA）。我们假设改变的TLR 4/TLR 2激活是IC/BPS的原因。 疼痛和阻断TLR 4和/或TLR 2激活可以逆转IC/BPS患者的膀胱炎疼痛。来测试我们 假设，我们将使用URO-OVA模型进行三个新的和综合的具体目标：1）识别 URO-OVA模型中膀胱炎疼痛中外周和中枢TLR 4/TLR 2激活的状态; 2）定量 全身性TLR 4抑制与慢性膀胱炎疼痛缓解，以确定全身性TLR 4的最佳水平 在URO-OVA模型中最大程度缓解疼痛的抑制; 3）开发TLR 4抑制组合疗法 用于URO-OVA模型中的膀胱炎疼痛。我们期望我们的研究将为 膀胱炎疼痛的机制和未来临床策略发展的基础研究平台， 治疗IC/BPS疼痛。从这项研究中获得的知识将有助于最终成功的临床护理 IC/BPS患者

PROJECT SUMMARY Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic and debilitating inflammatory condition of the urinary bladder characterized by the hallmark symptoms of pelvic pain in the absence of other identified etiologies for the symptom. IC/BPS patients also frequently have voiding dysfunction such as increased urinary frequency and urgency. This urologic condition is significant and severely affects quality of life. Its financial burden on the U.S. healthcare system is tremendous. Since the etiology of IC/BPS remains elusive, current treatments are largely empirical, often dissatisfactory, and vary in efficacy. Therefore, effort to develop new therapies for IC/BPS is greatly needed. Prior studies have suggested that altered Toll-like receptor (TLR) 4 activation may contribute significantly to the initiation and maintenance of heightened pain states in chronic pain conditions. TLR4 is expressed in numerous cell types including neuronal and non-neuronal cells in the central nervous system as well as immune (e.g. monocytes/macrophages) and other somatic cells (e.g. bladder epithelial cells) in the periphery. Once activated, TLR4 mediates proinflammatory cytokine production, leading to enhanced central and peripheral immune signaling and subsequent exaggerated nociceptive transmission. While the effect of TLR4 inhibition on chronic pain relief has been demonstrated in multiple animal models (e.g. inflammatory and neuropathic pain), this has not been explored in cystitis pain seen in IC/BPS patients. Recently, we identified a major role of altered TLR4/TLR2 activations in IC/BPS. Particularly, we observed that increased production of TLR4-mediated proinflammatory cytokines by peripheral blood mononuclear cells is significantly associated with greater pain severity and the extent of comorbid pain in IC/BPS patients. Consistent with our clinical findings, we found that cystitis pain is associated with elevated systemic and central TLR4/TLR2 inflammatory responses in our validated preclinical transgenic IC/BPS-like animal model (URO-OVA). We hypothesize that altered TLR4/TLR2 activations are responsible for IC/BPS pain and blocking TLR4 and/or TLR2 activation can reverse cystitis pain in IC/BPS patients. To test our hypothesis, we will use the URO-OVA model to conduct three novel and integrative Specific Aims: 1) Identify the states of peripheral and central TLR4/TLR2 activations in cystitis pain in the URO-OVA model; 2) Quantify systemic TLR4 inhibition versus chronic cystitis pain relief to determine the optimum level of systemic TLR4 inhibition for maximum pain relief in the URO-OVA model; 3) Develop TLR4 inhibition combination therapies for cystitis pain in the URO-OVA model. We anticipate that our study will provide new insights for the mechanisms of cystitis pain and a basic research platform for future development of clinical strategies for treatment of IC/BPS pain. Knowledge gained from this study will be useful for ultimately successful clinical care of IC/BPS patients.