Proteomic Characterization of IC Bladder

IC 膀胱的蛋白质组学表征

• 批准号: 7108521
• 负责人: Pradeep Tyagi
• 金额: $ 29.43万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7108521
• 关键词: animal tissue; antibody; biological signal transduction; biomarker; blood tests; diagnosis design /evaluation; disease /disorder etiology; immunocytochemistry; immunofluorescence technique; immunologic assay /test; interstitial cystitis; isoelectric point; laboratory mouse; laboratory rabbit; laboratory rat; nerve growth factors; nitric oxide; protein quantitation /detection; proteomics; two dimensional gel electrophoresis; urinalysis; urinary tract disorder diagnosis; western blottings

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.

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，其特征是慢性盆腔疼痛、尿频和尿急。据估计，它影响了美国 70 万至 100 万人；大约 90% 的报告患者是女性。 IC 的诊断主要基于症状，由于缺乏已证实的生物标志物，目前尚无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节中发挥核心作用。特定的核基质蛋白（NMP）已被确定为某些细胞类型或状态所独有。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鉴定与慢性膀胱炎相关的特定新标记物。神经生长因子 (NGF)、一氧化氮 (NO) 和促炎介质等多种药物已被证明对膀胱传入通路产生影响，这可能与慢性膀胱炎的频繁排尿和伤害性反应有关。因此，将测试两个假设：1）NMP 的改变是慢性刺激膀胱的特征，并且可以开发成膀胱疼痛综合征（例如 IC）的诊断标志物和/或治疗目标。 2）慢性膀胱炎干预NGF、NO和炎症通路后的功能改善与NMPs的变化相关。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，以确定与疾病相关的特定蛋白质。 2) 对与慢性刺激膀胱相关的特定核基质蛋白进行表征和测序，并产生针对这些标记物的抗体，并开发这方面的诊断测试。 3) 分析膀胱传入通路的几种调节剂 NGF、NO 和 IPD-1151 T 对与慢性囊炎性膀胱发病机制相关的特定 NMP 的影响。该研究项目的长期目标是确定新的标记物，这些标记物可用于敏感、特异性的 IC 测试/筛查，并可能在疾病的准确诊断甚至早期预测方面具有巨大价值。该研究项目的结果还可以确定药物治疗与膀胱疼痛综合征相关的慢性膀胱和/或盆腔疼痛的新分子靶点，为 IC 患者提供更好的治疗结果。

项目成果

Gender-based reciprocal expression of transforming growth factor-beta1 and the inducible nitric oxide synthase in a rat model of cyclophosphamide-induced cystitis.

• DOI: 10.1186/1476-9255-6-23
• 发表时间: 2009-08-19
• 期刊: Journal of inflammation (London, England)
• 作者: Tyagi P;Tyagi V;Yoshimura N;Witteemer E;Barclay D;Loughran PA;Zamora R;Vodovotz Y
• 通讯作者: Vodovotz Y