Role of TNF in Bladder Inflammation

TNF 在膀胱炎症中的作用

• 批准号: 7983876
• 负责人: David J Klumpp
• 金额: $ 9.42万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-11-19 至 2011-11-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7983876
• 关键词: Acute; American; Antibodies; Biological Markers; Biopsy Specimen; Bladder; Chronic; Chronic Cystitis; Clinic; Clinical Research; Control Groups; Cystitis; Data; Databases; Diagnosis; Disease; Disease Marker; Epidemiology; Etiology; Functional disorder; Future; Genetic; Human; Inflammation; Inflammatory; Interstitial Cystitis; Knockout Mice; Lamina Propria; Lesion; Mediating; Mediator of activation protein; Modality; Modeling; Monitor; Morbidity - disease rate; Mus; Pain; Partner in relationship; Pathogenesis; Pathologic; Pathology; Patients; Pelvic Pain; Physiology; Pilot Projects; Positioning Attribute; Predisposition; Prevalence; Process; RANTES; RANTES receptor; Recruitment Activity; Relative (related person); Role; Sampling; Specificity; Staining method; Stains; Study Subject; Suid Herpesvirus 1; Symptoms; Syndrome; Testing; Therapeutic; Therapeutic Intervention; Treatment Efficacy; Tumor Necrosis Factor-alpha; Urinary tract infection; Urine; Urology; Urothelium; Visit; Wild Type Mouse; base; chemokine; chronic pelvic pain; cohort; effective therapy; epidemiology study; immunoreactivity; innovation; mast cell; mouse model; new therapeutic target; novel; prostatitis; research study; response; success; therapeutic target; trafficking; urinary; validation studies

DESCRIPTION (provided by applicant): Interstitial cystitis (IC) is a syndrome that afflicts up to 1 million Americans with grave morbidity due to severe pelvic pain and voiding dysfunction. Although IC is often considered a chronic inflammatory disease of the urinary bladder, the etiology of IC is unknown, no effective therapies exist, and no convenient biomarkers exist. The lack of a convenient biomarker complicates both IC diagnosis and monitoring responses to therapy. Recent pathologic studies have shown that patient symptoms are correlated with lesions of the urothelium that lines the bladder and accumulation of mast cells in the underlying lamina propria. Inflammation due to neurogenic mechanisms has been postulated as one mechanism of IC pathogenesis. We developed a mouse model of neurogenic cystitis that recapitulates key aspects of IC including bladder-specific pain, altered bladder physiology, urothelial lesions, and accumulation of lamina propria mast cells. We find that bladder pathology requires expression of RANTES, a mast cell chemokine that is induced in the urothelium by tumor necrosis factor alpha (TNF). Importantly, we find that RANTES is also elevated in IC urines, thus representing a novel urine biomarker for IC. In our murine model, inhibiting RANTES or TNF blocks lamina propria mast cell accumulation and bladder pathology. Therefore, we hypothesize that RANTES is a urinary biomarker that is elevated in a subset of IC patients, and anti-RANTES therapy represents a novel therapeutic target for treating RANTES-associated IC. We will test this hypothesis by first establishing the prevalence of elevated RANTES in urines of IC patients and control groups by taking advantage of our unique access to a cohort of 600 urine samples from a nationwide IC epidemiology study (Aim 1). We will then quantify the efficacy of mechanistically-directed therapies in two complementary murine models. Anti-RANTES and anti-TNF will be evaluated for inhibition of bladder pathology and pathophysiology in acute neurogenic cystitis (Aim 2). Anti-RANTES and anti-TNF will then be evaluated in a chronic, urothelium-specific TNF cystitis model (Aim 3). This innovative approach determining the prevalence of RANTES as a novel chemokine biomarker and then testing rationally directed therapeutic interventions in murine models has a high likelihood of success. This project lays the ground for future clinical studies of IC therapies and provides a novel phenotypic biomarker for genetic studies.Interstitial cystitis (IC) is a syndrome that afflicts up to 1 million Americans with grave morbidity due to severe pelvic pain and voiding dysfunction, yet the etiology of IC is unknown, and no convenient biomarkers exist. This project will determine the prevalence of RANTES as a novel IC biomarker in urines and then quantify the efficacy of mechanistically-directed therapies in murine models.

描述（由申请人提供）：间质性膀胱炎（IC）是一种因严重骨盆疼痛和排尿功能障碍导致的严重发病率高达100万美国人的综合征。虽然IC通常被认为是膀胱的慢性炎性疾病，但IC的病因尚不清楚，没有有效的治疗方法，也没有方便的生物标志物。缺乏方便的生物标志物使IC诊断和监测对治疗的反应复杂化。最近的病理学研究表明，患者的症状与衬在膀胱上的尿路上皮的病变和肥大细胞在下面的固有层中的积聚相关。神经源性机制引起的炎症被认为是IC发病机制之一。我们开发了一种神经源性膀胱炎小鼠模型，该模型概括了IC的关键方面，包括膀胱特异性疼痛、膀胱生理学改变、尿路上皮病变和固有层肥大细胞积聚。我们发现，膀胱病理需要表达RANTES，肥大细胞趋化因子，诱导肿瘤坏死因子α（TNF）在尿路上皮。重要的是，我们发现RANTES在IC尿液中也升高，因此代表了IC的新尿液生物标志物。在我们的小鼠模型中，抑制RANTES或TNF阻断固有层肥大细胞积聚和膀胱病理。因此，我们假设RANTES是一种尿生物标志物，在IC患者的子集中升高，抗RANTES治疗代表了治疗RANTES相关IC的新治疗靶点。我们将通过首先确定IC患者和对照组尿液中RANTES升高的患病率来验证这一假设，这是利用我们从全国IC流行病学研究中获得的600份尿液样本的独特访问权限（目的1）。然后，我们将在两个互补的小鼠模型中量化机械定向疗法的疗效。将评价抗RANTES和抗TNF对急性神经源性膀胱炎的膀胱病理学和病理生理学的抑制作用（目的2）。然后在慢性、尿路特异性TNF膀胱炎模型中评价抗RANTES和抗TNF（目的3）。这种创新方法 确定RANTES作为新型趋化因子生物标志物的流行率，然后在小鼠模型中测试合理定向的治疗干预 成功的可能性很大该项目为IC治疗的未来临床研究奠定了基础，并为遗传学研究提供了一种新的表型生物标志物。间质性膀胱炎（IC）是一种困扰多达100万美国人的综合征，由于严重的骨盆疼痛和排尿功能障碍，IC的病因不明，没有方便的生物标志物存在。该项目将确定RANTES作为尿中新型IC生物标志物的流行率，然后量化小鼠模型中机械定向治疗的疗效。

项目成果

Ca(2+)/calmodulin-dependent protein kinase II is associated with pelvic pain of neurogenic cystitis.

Ca(2)/钙调蛋白依赖性蛋白激酶 II 与神经源性膀胱炎的盆腔疼痛有关。

• DOI: 10.1152/ajprenal.00077.2012
• 发表时间: 2012
• 期刊: American journal of physiology. Renal physiology
• 作者: Yang,Wenbin;Rudick,CharlesN;Hoxha,Eneda;Allsop,StephenA;Dimitrakoff,JordanD;Klumpp,DavidJ
• 通讯作者: Klumpp,DavidJ