Role of TNF in Bladder Inflammation

描述（由申请人提供）：间质性膀胱炎（IC）是一种折磨着多达100万美国人的综合征，由于严重的盆腔疼痛和排尿功能障碍而严重发病率。虽然IC通常被认为是膀胱的慢性炎症性疾病，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诊断和对治疗反应的监测复杂化。最近的病理研究表明，患者的症状与膀胱内尿路上皮的病变和固有层下肥大细胞的积累有关。神经源性炎症被认为是IC发病的一种机制。我们建立了一个神经源性膀胱炎的小鼠模型，该模型概括了IC的关键方面，包括膀胱特异性疼痛、膀胱生理改变、尿路上皮病变和固有层肥大细胞的积累。我们发现膀胱病理需要RANTES的表达，RANTES是一种在尿路上皮中由肿瘤坏死因子（TNF）诱导的肥大细胞趋化因子。重要的是，我们发现RANTES在IC尿中也升高，因此代表了IC的一种新的尿液生物标志物。在我们的小鼠模型中，抑制RANTES或TNF可阻断固有层肥大细胞积聚和膀胱病理。因此，我们假设RANTES是一种尿液生物标志物，在一部分IC患者中升高，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份尿液样本的独特途径，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（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功效。将评估抗rantes和抗tnf对急性神经源性膀胱炎膀胱病理和病理生理的抑制作用（目的2）。抗rantes和抗TNF将在慢性尿路特异性TNF膀胱炎模型中进行评估（Aim 3）。这种创新的方法确定了RANTES作为一种新的趋化因子生物标志物的流行程度，然后在小鼠模型中测试合理指导的治疗干预措施，具有很高的成功可能性。该项目为未来IC治疗的临床研究奠定了基础，并为基因研究提供了一种新的表型生物标志物。间质性膀胱炎（IC）是一种折磨多达100万美国人的综合征，由于严重的盆腔疼痛和排尿功能障碍而严重发病率，但IC的病因尚不清楚，也没有方便的生物标志物存在。该项目将确定RANTES在尿液中作为一种新的IC生物标志物的普遍性，然后在小鼠模型中量化机械定向治疗的疗效。

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.