UV, Neuropeptides, Histamine and Buruli Ulcer Disease

紫外线、神经肽、组胺和布鲁里溃疡病

• 批准号: 6954285
• 负责人: RHIAN B COPE
• 金额: $ 7.08万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6954285
• 关键词: Mycobacterium; bacterial disease; calcitonin gene related peptide; capsaicin; cimetidine; cyproheptadine; disease /disorder etiology; emerging infectious disease; guinea pigs; histamine; immunocytochemistry; immunopathology; indomethacin; skin infection; skin ulcer; ultraviolet radiation; urocanate

DESCRIPTION (provided by applicant): Human Buruli ulcer disease (BUD) is a severe skin disease caused by predominantly extracellular infection with Mycobacterium ulcerans (MU). This emergent, high-morbidity disease causes destructive skin ulcers that may cover up to 15% of the body surface area. Secondary infection of the ulcers is extremely rare. Effective treatment requires multiple surgical excisions and skin grafting that often results in significant deformity or disability. Infection of the hairless guinea pig (GP) with virulent MU mimics BUD. The PI has shown that pre-infection exposure to ultraviolet -B (UV) exacerbates BUD and suppresses delayed-type hypersensitivity (DTH) responses to MU in the GP model. The PI has also demonstrated that topical pre- infection exposure to cis-urocanic acid (cUCA), an initiator of photoimmunosuppression, mimics the effects of UV on BUD. A key pathway in UV-induced immunosuppression is the cUCA-neuropeptide pathway. The relevance of this pathway to the effects of UV on infectious disease in general, and BUD in particular, is unknown. This represents a critical gap in the knowledge base. Thus, the aim of this proposal is to test the hypothesis that blocking of the UV-cUCA-neuropeptide-photoimmunosuppression pathway will prevent UV- induced enhancement of MU infection in the hairless guinea pig model of Buruli ulcer disease. To test our hypothesis, 2 experiments will be performed: (1) does pre-irradiation capscaicin-mediated neuropeptide depletion block UV-augmentation of BUD?; and (2) does pre- and post-irradiation treatment with calcitonin gene related peptide receptor antagonists or H1 and H2 histamine antagonists or indomethacin block UV- augmentation of BUD. Importantly, the incorporation of relevant control groups in the proposed experiments will allow for the examination of the role of the neuropeptide-histamine-prostanoid pathway during the pathogenesis of MU infection in non-irradiated animals. Irrespective of the outcomes of these experiments, new and important information on BUD pathogenesis will be obtained.

描述（由申请方提供）：人布鲁里溃疡病（BUD）是一种严重的皮肤病，主要由溃疡分枝杆菌（MU）的细胞外感染引起。这种突发的高发病率疾病导致破坏性皮肤溃疡，可能覆盖高达15%的体表面积。溃疡的继发感染是非常罕见的。有效的治疗需要多次手术切除和植皮，这往往会导致严重的畸形或残疾。用毒性MU感染无毛豚鼠（GP）模拟BUD。PI已表明，感染前暴露于紫外线-B（UV）可加重BUD并抑制GP模型中对MU的迟发型超敏反应（DTH）。PI还证明，局部感染前暴露于顺式尿刊酸（cUCA）（光免疫抑制的引发剂）可模拟UV对BUD的影响。UV诱导的免疫抑制的关键途径是cUCA-神经肽途径。这一途径与紫外线对一般传染病的影响，特别是与BUD的影响的相关性尚不清楚。这是知识基础中的一个重大空白。因此，本提案的目的是检验以下假设：阻断UV-cUCA-神经肽-光免疫抑制途径将防止布鲁里溃疡病无毛豚鼠模型中UV诱导的MU感染增强。为了验证我们的假设，将进行两个实验：（1）照射前辣椒素介导的神经肽耗竭是否阻断BUD？的UV增强;和（2）照射前后用降钙素基因相关肽受体拮抗剂或H1和H2组胺拮抗剂或吲哚美辛阻断BUD的UV增强。重要的是，在拟议的实验中纳入相关对照组将允许检查神经肽-组胺-前列腺素途径在非辐照动物MU感染发病过程中的作用。无论这些实验的结果如何，都将获得关于BUD发病机制的新的重要信息。