Chemokine Mechanisms in Chronic Pelvic Pain

慢性盆腔疼痛的趋化因子机制

• 批准号: 8141242
• 负责人: PRAVEEN THUMBIKAT
• 金额: $ 31.75万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8141242
• 关键词: Accounting; American; Animal Model; Anogenital region; Antibodies; Area; Attenuated; Autoimmune Process; Biological Markers; Bone Marrow; Bone Marrow Transplantation; CCL2 gene; Calcium; Categories; Cell Count; Cell Culture Techniques; Cell Degranulation; Cell physiology; Cells; Chemotaxis; Chronic Prostatitis; Clinic; Clinical; Clinical Research; Conditioned Culture Media; Development; Diagnosis; Disease; Dysuria; Epithelial; Epithelium; Etiology; Functional disorder; Future; Hematopoietic; Histamine; Histamine Receptor; Hormonal; Human; Immunohistochemistry; In Vitro; Inflammation; Inflammatory; Injury; Interstitial Cystitis; Knockout Mice; Lead; Macrophage Inflammatory Protein-1; Mast Cell Stabilizer; Measures; Mediating; Modeling; Monocyte Chemoattractant Protein-1; Morbidity - disease rate; Mus; Nerve Growth Factors; Neuronal Plasticity; Neurons; Neuropathy; Outpatients; Pain; Pathogenesis; Patients; Pelvic Pain; Peripheral; Peripheral Nervous System; Primary Care Physician; Process; Prostate; Prostatic; Quality of life; Role; Source; Specimen; Stromal Cells; Substance P; Symptoms; Syndrome; Testing; Testis; Therapeutic; Time; Tissues; Treatment Efficacy; Tryptase; United States; United States National Institutes of Health; Universities; Up-Regulation; Urology; Visit; beta-n-acetylhexosaminidase; cell type; chemokine; chronic pain; chronic pelvic pain; cohort; cytokine; density; disease diagnosis; efficacy testing; human MCP1 protein; indexing; mast cell; men; neurotrophic factor; neutralizing antibody; pain behavior; penis; prostatitis; public health relevance; receptor; reconstitution; release factor; translational study

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.

描述（由申请人提供）：慢性骨盆疼痛是慢性骨盆疼痛综合征（CPP）的标志，这是前列腺炎的非细菌类别，是美国男性发病率的重要来源。 CPP的病因和发病机理尚不清楚，但已被认为包括多种原因。缺乏方便的生物标志物和对CPP病理生理学的更好理解具有复杂的疾病诊断和治疗。我们将MCP-1和MIP-11鉴定为CPP患者表达的前列腺分泌（EP）中的潜在生物标志物。 EPS中的MCP-1和MIP-11水平鉴定出精度为90％且MIP-11水平的CPP患者与美国国立卫生研究院的临床疼痛亚域评分相关。 我们利用了前列腺炎鼠模型中骨盆疼痛的定量测量，以表征前列腺特异性的慢性骨盆疼痛，让人联想到人CPP。在鼠模型中，MIP-11和MCP-1在20天时的承诺内表达增加。抗MCP-1或抗MIP-11中和抗体可显着减少抗MCP-1小鼠慢性骨盆疼痛的发育也有效。除趋化因子上调外，还观察到被激活的肥大细胞数量增加。综上所述，这些研究使我们假设MCP-1和MIP-11等趋化因子有助于募集和激活肥大细胞，从而导致周围神经元敏化和慢性骨盆疼痛的发展。我们将以四个特定目标提出假设。我们将进行严格的临床研究，以验证MCP-1和MIP-11和MAST细胞胰蛋白酶作为人类CPP的生物标志物的使用，并将其水平与CPP症状相关联。我们将在回顾性收集的人前列腺组织切片中量化肥大细胞，并将MCP-1和MIP-11表达定位。 MCP-1和MIP-11表达的来源以及肥大细胞的作用将在动物模型中解剖。体外培养模型将检查前列腺上皮/基质与肥大细胞的相互作用。最后，我们将测试抑制MCP-1，MIP-11和肥大细胞功能减少慢性骨盆疼痛的靶向疗法的功效。该项目将为针对CPP慢性骨盆疼痛的机制的疗法的未来翻译研究奠定基础。 公共卫生相关性：慢性骨盆疼痛是慢性骨盆疼痛综合征（CPP）的标志，这是前列腺炎的非细菌类别，是美国男性发病率的重要来源。 CPP的原因尚不清楚，并且缺乏方便的生物标志物来诊断该综合征。该项目将验证生物标志物以诊断CPP，并进行研究以了解疾病症状背后的机制。最后，该项目将测试针对慢性骨盆疼痛的新疗法在动物模型中的功效。