Proteomic Characterization of IC Bladder

描述(申请人提供)：间质性膀胱炎(IC)是一种病因不明的痛性膀胱综合征，以慢性盆腔疼痛、尿频和尿急为特征。据估计，在美国有70万到100万人受到影响；据报道，大约90%的患者是女性。IC的诊断主要基于症状，因为由于缺乏已证实的生物标志物，目前还没有可用的血液或尿液测试。核基质是细胞核的结构支架，在调节重要的细胞过程中起着核心作用。特定的核基质蛋白(NMP)被认为是某些细胞类型或状态所特有的。尽管细胞中不同蛋白质的估计数量可能超过同一细胞中估计的基因数量，但蛋白质是细胞病理生理学中的功能参与者。因此，我们建议使用蛋白质组学方法来识别与慢性膀胱炎相关的特定新标记物。一些药物，如神经生长因子(NGF)、一氧化氮(NO)和促炎介质，已被证明在膀胱传入通路中发挥作用，这可能与慢性膀胱炎的频繁排尿和伤害性反应有关。因此，将检验两个假说：1)NMPs的改变是慢性刺激膀胱的特征，可以发展为痛性膀胱综合征(如IC)的诊断标志和/或治疗靶点。2)慢性膀胱炎患者NGF、NO及炎症通路干预后功能改善与NMPs变化有关。为了解决这些假设，我们提出了以下具体目标：1)与正常对照相比，对慢性刺激患者膀胱核基质蛋白成分进行全面分析，以确定与疾病相关的特定蛋白质。2)确定与慢性刺激膀胱相关的特定核基质蛋白的特征和序列，并针对这些标志物提高抗体，并开发这方面的诊断试验。3)分析几种膀胱传入通路调节剂NGF、NO和IPD-1151T对慢性膀胱炎发病机制中特异性NMPs的影响。这项研究项目的长期目标是确定新的标记物，这些标记物可以用于对IC的敏感、特异的测试/筛查，并可能在疾病的准确诊断甚至早期预测方面证明具有巨大的价值。这一研究项目的结果还可以确定与疼痛膀胱综合征相关的慢性膀胱和/或盆腔疼痛的药物治疗的新分子靶点，为IC患者提供更好的结果。

DESCRIPTION (provided by applicant): Interstitial cystitis (IC) is a painful bladder syndrome of unknown etiology, characterized by chronic pelvic pain, urinary frequency and urgency. It affects an estimated 700,000 to one million people in the United States; approximately 90% of the reported sufferers are women. Diagnosis of IC is primarily based on symptoms, as there are no currently available blood or urine tests due to the lack of demonstrated biological markers. The nuclear matrix is the structural scaffolding of the cell nucleus and plays a central role in the regulation of important cellular processes. Specific nuclear matrix proteins (NMPs) have been identified as unique to certain cell types or states. Although the estimated number of different proteins in a cell might outnumber the estimated number of genes in the same cell, proteins are the functional players in cell pathophysiology. Therefore, we propose to use a proteomic approach to identify specific new markers related to chronic cystitis. Several agents, such as Nerve Growth Factor (NGF), nitric oxide (NO) and proinflammatory mediators, have been shown to exert an effect in bladder afferent pathways that could be related to frequent voiding and nociceptive responses in chronic cystitis. Thus, two hypotheses will be tested: 1) Alterations in NMPs are characteristic of the bladder with chronic irritation and can be developed into diagnostic markers and/or treatment targets for painful bladder syndrome such as IC. 2) Functional improvement of chronic cystitis after intervention on NGF, NO, and inflammatory pathways, is associated with changes in NMPs. To address these hypotheses, we propose the following Specific Aims: 1) to perform a comprehensive analysis of the nuclear matrix protein composition of the bladder with chronic irritation in comparison to normal controls to identify specific proteins associated with the disease. 2) to characterize and sequence specific nuclear matrix proteins associated with bladders with chronic irritation and to raise antibodies against these markers and to develop diagnostics tests in this regard. 3) to analyze the effect of several modulators of the bladder afferent pathway, NGF, NO and IPD-1151 T, on specific NMPs associated with the pathogenesis of chronic cystitic bladder. The long-term objectives of this research project are to identify new markers that can be used in sensitive, specific test/screens for IC and may prove of immense value in the accurate diagnosis, and even early prediction, of disease. The results of this research project could also identify new molecular targets of drug therapy for chronic bladder and/or pelvic pain associated with painful bladder syndromes, offering a better outcome for patients with IC.