Amyloid Precursor Proteins in Sarcoidosis

结节病中的淀粉样前体蛋白

• 批准号: 6819461
• 负责人: David R Moller
• 金额: $ 24.53万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-10 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6819461
• 关键词: B lymphocyte; Mycobacterium; amyloid proteins; antigens; clinical research; disease /disorder etiology; gene expression; genetic regulation; genetically modified animals; granuloma; helper T lymphocyte; host organism interaction; human subject; immunogenetics; interleukin 12; interleukin 18; laboratory mouse; laboratory rat; laser capture microdissection; matrix assisted laser desorption ionization; molecular pathology; patient oriented research; protein structure function; sarcoidosis; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that involves the lungs in over 90% of affected individuals and may cause end-stage pulmonary fibrosis and death. The pathologic hallmark of sarcoidosis is non-caseating granulomatous inflammation. A major step in understanding sarcoidosis would be the identification of specific host proteins that regulate granuloma formation in this disease. Recently, using a limited proteomic approach with matrix-associated laser desorption/ionization-time of flight (MALDI-TOF) mass spectroscopy, we identified Mycobacterium tuberculosis catalase- eroxidase as a tissue antigen and target of the immune response in sarcoidosis, supporting a microbial, etiologyof sarcoidosis. Using this same proteomic approach, our preliminary studies have identified the amyloid precursor protein, serum amyloid A (SAA), as a potentially critical host protein regulating granuloma formation in sarcoidosis. SAA is expressed in a well-defined, often intense pattern of staining in epithelioid granulomas in sarcoidosis not typified by several other granulomatous disorders. SAA is highly inducible in mononuclear cells by mycobacterial organisms and has both pro- and anti-inflammatory properties. Our preliminary data suggests SAA promotes Th1 immune responses in sarcoidosis by stimulating expression of TNF, IL18, and possibly, IL12. Our hypothesis is that SAA, as part of an innate immune response, critically regulates granuloma formation in sarcoidosis. The goal of this application is to examine the roles of SAA in regulating granuloma formation in sarcoidosis--as a contributor to protein aggregation at sites of granuloma formation, as a promoter of Th1 immune responses, and as a critical regulator of Th1 mediated granulomatous inflammation in a rodent model of sarcoidosis. These studies have the potential to provide evidence for a critical host protein and pathway, linked to etiologic antigens, that regulates the origin and fate of sarcoidosis granulemas, thus becoming a potential target of therapeutic intervention.

描述（由申请人提供）： 结节病是一种病因不明的多系统肉芽肿性疾病，90%以上的患者累及肺部，可能导致终末期肺纤维化和死亡。结节病的病理特征是非干酪化性肉芽肿性炎症。了解结节病的一个主要步骤是确定在这种疾病中调节肉芽肿形成的特定宿主蛋白。最近，我们利用基质相关激光解吸/电离飞行时间（MALDI-TOF）质谱的有限蛋白质组学方法，鉴定了结核分枝杆菌过氧化氢酶-过氧化物酶作为结节病免疫反应的组织抗原和靶点，支持结节病的微生物病因学。使用相同的蛋白质组学方法，我们的初步研究已经确定了淀粉样前体蛋白，血清淀粉样蛋白A（SAA），作为一个潜在的关键宿主蛋白调节肉芽肿形成的结节病。SAA在结节病的上皮样肉芽肿中表达为界限清楚的强染色模式，而在其他几种肉芽肿性疾病中不典型。SAA在单核细胞中可被分枝杆菌生物体高度诱导，并且具有促炎和抗炎特性。我们的初步数据表明SAA通过刺激TNF、IL 18和可能的IL 12的表达来促进结节病中的Th 1免疫应答。我们的假设是，SAA，作为先天免疫反应的一部分，严重调节结节病肉芽肿的形成。本申请的目的是研究SAA在调节结节病肉芽肿形成中的作用-作为肉芽肿形成部位蛋白聚集的贡献者，作为Th 1免疫应答的促进剂，以及作为啮齿动物结节病模型中Th 1介导的肉芽肿性炎症的关键调节剂。这些研究有可能为与病原抗原相关的关键宿主蛋白和途径提供证据，该蛋白和途径调节结节病肉芽肿的起源和命运，从而成为治疗干预的潜在靶点。