Role of propionibacteria in sarcoidosis

丙酸杆菌在结节病中的作用

• 批准号: 6816509
• 负责人: STEPHEN Lloyd TILLEY
• 金额: $ 14.6万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6816509
• 关键词: Propionibacterium; clinical research; disease /disorder etiology; disease /disorder model; host neoplasm interaction; human subject; in situ hybridization; laboratory mouse; laser capture microdissection; lymph node neoplasm; microorganism culture; model design /development; pathologic process; polymerase chain reaction; sarcoidosis; transfection /expression vector

DESCRIPTION (provided by applicant): The objective of this proposal is to determine if Propionibacteria are etiologically important to the development of sarcoidosis in the United States (Aim 1), and to develop a mouse model of sarcoidosis using this bacterium (Aim 2). Several lines of evidence suggest that this anaerobic bacteria may be involved in the pathogenesis of disease. First Propionibacteria have been identified by culture and PCR in a high percentage of sarcoid lymph nodes from Japanese and European patients, and studies with in situ molecular probes detected Propionibacteria within sarcoid granulomas. Second, antibiotics effective against this organism showed remarkable efficacy in a small group of patients with cutaneous sarooidosis. Finally, animals exposed to this bacterium develop granulomatous inflammation similar to sarcoidosis. In Aim 1 we will look for evidence of Propionibacteria by performing quantitative PCR, with probes specific for this organism, on DNA from granulomas obtained by laser capture microscopy from parffin-embedded samples. We will also look for Propionibacteria by in situ hybridization. Finally, we will attempt to culture the organism from tissue obtained from patients undergoing diagnostic evaluation. Cultured bacteria will be characterized from patients with acute-resolving and chronic-persistent disease to see if the bacterial factors contribute to clinical phenotype. Cultured bacteria will also be used for inoculation in mice to produce an animal model. The initiation, maintenance, and resolution of granulomatous inflammation in mice of several different strains will be assessed following exposure to Propionibacteria. These experiments will allow us to look at host factors as determinants of clinical phenotype. Multiple organs will be evaluated including the lungs, lymph nodes, liver, spleen, heart, brain, and eyes, and skin to determine whether host factors or bacterial factors are important for specific organ involvement. Future directions will include a placebo-controlled trial of tetracyclines for sarcoidosis if Propionibacteria are identified.

描述（由申请人提供）： 该提案的目的是确定丙酸杆菌在美国的病因上是否重要（AIM 1），并使用该细菌开发小鼠结节病模型（AIM 2）。几条证据表明，这种厌氧细菌可能参与疾病的发病机理。通过培养和PCR鉴定了首次丙酸杆菌，其中包括日本和欧洲患者的结节淋巴结的高比例，并研究了在曲杆菌肉芽肿内检测到的原位分子探针的研究。其次，对这种生物的有效抗生素在一小组皮肤病患者中表现出显着的功效。最后，暴露于这种细菌的动物会形成类似于结节病的肉芽肿性炎症。在AIM 1中，我们将通过进行定量PCR来寻找丙酸杆菌的证据，并用该生物特异性的探针，对通过激光捕获显微镜从Parffin填充的样品获得的颗粒的DNA进行探针。我们还将通过原位杂交寻找丙酸杆菌。最后，我们将尝试从接受诊断评估的患者获得的组织中培养生物体。培养的细菌将由患有急性分辨和慢性疾病的患者进行特征，以查看细菌因子是否有助于临床表型。培养的细菌也将用于接种小鼠，以产生动物模型。在暴露于丙酸杆菌后，将评估几种不同菌株的小鼠肉芽肿性炎症的启动，维持和分辨率。这些实验将使我们能够将宿主因子视为临床表型的决定因素。将评估多个器官，包括肺，淋巴结，肝脏，脾脏，心脏，脑和眼睛以及皮肤，以确定宿主因素或细菌因子是否对特定器官的参与很重要。未来的方向将包括鉴定出丙杆菌的四环素的安慰剂对照试验。