Chemokine Mechanisms in Chronic Pelvic Pain

描述(申请人提供)：慢性盆腔疼痛是慢性盆腔疼痛综合征(CPPS)患者的特征，这是一种非细菌性前列腺炎，是美国男性发病率的重要来源。CPPS的病因和发病机制尚不清楚，但已被推测包括多种原因。缺乏方便的生物标志物和对CPPS病理生理的更好理解使疾病的诊断和治疗变得复杂。我们确定MCP-1和MIP-11是CPPS患者前列腺液(EPS)表达的潜在生物标志物。EPS中MCP-1和MIP-11水平与美国国立卫生研究院慢性前列腺炎症状指数的临床疼痛亚域评分相关，准确率为90%。我们在前列腺炎小鼠模型中利用盆腔疼痛的定量测量来表征前列腺特异性的慢性盆腔疼痛，使人联想到人类CPPS。MIP-11和MCP-1在20d模型小鼠前列腺内的表达增加。抗MCP-1或抗MIP-11中和抗体可显著减少小鼠慢性盆腔疼痛的发展，且抗MCP-1也具有治疗作用。除了趋化因子上调外，还观察到被激活的肥大细胞数量增加。综上所述，这些研究引导我们假设，趋化因子如MCP-1和MIP-11有助于肥大细胞的招募和激活，导致周围神经元敏化和慢性盆腔疼痛的发展。我们将带着四个具体目标继续我们的假设。我们将进行严格的临床研究，以验证MCP-1、MIP-11和肥大细胞类胰蛋白酶作为人类CPPS的生物标志物的有效性，并将它们的水平与CPPS症状相关联。我们将量化肥大细胞并定位MCP-1和MIP-11在回溯收集的人类前列腺组织切片中的表达。MCP-1和MIP-11的表达来源和肥大细胞的作用将在动物模型中进行解剖。体外培养模型将检测前列腺上皮/间质与肥大细胞的相互作用。最后，我们将测试抑制MCP-1、MIP-11和肥大细胞功能的靶向治疗在减轻慢性盆腔疼痛方面的效果。该项目将为未来针对慢性盆腔疼痛在CPPS中的潜在机制的治疗方法的翻译研究奠定基础。 公共卫生相关性：慢性盆腔疼痛是慢性盆腔疼痛综合征(CPPS)患者的特征，这是一种非细菌性前列腺炎，是美国男性发病率的重要来源。CPPS的病因尚不清楚，目前还缺乏方便的生物标志物来诊断这种综合征。该项目将验证诊断CPPS的生物标记物，并进行研究以了解疾病症状背后的机制。最后，该项目将在动物模型中测试针对慢性盆腔疼痛的新疗法的有效性。

DESCRIPTION (provided by applicant): Chronic pelvic pain is the hallmark of patients with chronic pelvic pain syndrome (CPPS), a non- bacterial category of prostatitis that is a significant source of morbidity in American men. The etiology and pathogenesis of CPPS remains unknown but has been postulated to include a multitude of causes. The lack of convenient biomarkers and a better understanding of CPPS pathophysiology have complicated disease diagnosis and therapy. We identified MCP-1 and MIP-11 as potential biomarkers in expressed prostatic secretions (EPS) of patients with CPPS. MCP-1 and MIP-11 levels in EPS identified CPPS patients with an accuracy of 90% and MIP-11 levels were correlated with the clinical pain subdomain score of the National Institutes of Health Chronic Prostatitis Symptom Index. We utilized quantitative measures of pelvic pain in murine models of prostatitis to characterize prostate-specific, chronic pelvic pain reminiscent of human CPPS. Intra-prostatic expression of MIP-11 and MCP-1 at 20 days was increased in the murine model. Anti-MCP-1 or anti-MIP-11 neutralizing antibody significantly reduced the development of chronic pelvic pain in mice with Anti-MCP-1 also being effective therapeutically. In addition to chemokine upregulation, increased numbers of mast cells that were activated was also observed. Taken together, these studies lead us to hypothesize that chemokines such as MCP-1 and MIP-11 contribute to the recruitment and activation of mast cells leading to peripheral neuronal sensitization and development of chronic pelvic pain. We will pursue our hypothesis with four specific aims. We will perform rigorous clinical studies to validate the use of MCP-1 and MIP-11 and mast cell tryptase as biomarkers for CPPS in humans and correlate their levels with CPPS symptoms. We will quantify mast cells and localize MCP-1 and MIP-11 expression in retrospectively collected human prostate tissue sections. The source of MCP-1 and MIP-11 expression and the role of mast cells will be dissected in the animal model. In vitro culture models will examine prostate-epithelia/stroma interactions with mast cells. Finally, we will test the efficacy of targeted therapies that inhibit MCP-1, MIP-11 and mast cell function in reducing chronic pelvic pain. This project will lay the ground for future translational studies of therapies that target the mechanisms underlying chronic pelvic pain in CPPS. PUBLIC HEALTH RELEVANCE: Chronic pelvic pain is the hallmark of patients with chronic pelvic pain syndrome (CPPS), a non-bacterial category of prostatitis that is a significant source of morbidity in American men. The cause of CPPS is unknown and there is a lack of convenient biomarkers for diagnosis of this syndrome. This project will validate biomarkers for the diagnosis of CPPS and also perform studies to understand the mechanisms behind disease symptoms. Finally, this project will test the efficacy of new therapies targeting chronic pelvic pain in animal models.