Proteomic Characterization of IC Bladder

描述（由申请人提供）：间质性膀胱炎（IC）是一种病因不明的膀胱疼痛综合征，以慢性盆腔疼痛、尿频和尿急为特征。在美国，估计有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，由于缺乏明确的生物标志物，目前没有可用的血液或尿液检测。核基质是细胞核的结构支架，在重要细胞过程的调控中起着核心作用。特定的核基质蛋白（NMPs）已被确定为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基因的估计数量，但蛋白质在细胞病理生理中起着重要的作用。因此，我们建议使用蛋白质组学方法来鉴定与慢性膀胱炎相关的特异性新标志物。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，可能与慢性膀胱炎患者频繁排尿和伤害性反应有关。因此，我们将检验两种假设：1)nmp的改变是膀胱慢性刺激的特征，可以发展为膀胱疼痛综合征（如IC）的诊断标志物和/或治疗靶点。2)干预NGF、NO和炎症途径后慢性膀胱炎的功能改善与nmp的改变有关。为了解决这些假设，我们提出以下具体目标：1)与正常对照相比，对慢性刺激膀胱的核基质蛋白组成进行全面分析，以确定与该疾病相关的特定蛋白质。2)对与慢性刺激膀胱相关的特异性核基质蛋白进行表征和测序，培养针对这些标记物的抗体，并在这方面开发诊断测试。3)分析几种膀胱传入通路调节剂NGF、NO和IPD-1151 T对慢性膀胱发病相关特异性NMPs的影响。这项研究项目的长期目标是确定新的标记物，这些标记物可用于IC的敏感、特异性测试/筛选，并可能证明在准确诊断甚至早期预测疾病方面具有巨大价值。本研究项目的结果还可以确定与膀胱疼痛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.