The Role of BBI36/38 in Lyme Disease Pathogenesis

描述(由申请人提供)：该提案描述了一项为期5年的培训计划，旨在提供教育经验和实验室培训，以便在传染病基础研究领域成为一名成功的独立调查员。候选人之前的研究活动有很长的历史，这项提议包括生物统计学和研究设计方面的正式课程，这将补充候选人以前的研究生工作。实验室工作将涵盖目前的能力领域，并允许在免疫组织化学、螺旋体的遗传操作和传染病的动物模型方面进行进一步培训。实验蛋白质组学和分子发病机制领域的专家詹姆斯·卡罗尔博士将与该机构的一个由高级研究人员组成的咨询委员会密切合作，指导候选人。 莱姆病是美国报告的最常见的媒介传播感染，在过去10年中发病率翻了一番。伯氏疏螺旋体是莱姆病的螺旋体病原体，在扁虱-哺乳动物感染周期中调节其膜蛋白。我们观察到，BBA71是PGF膜蛋白家族的成员，在模拟哺乳动物感染的条件下表达增加。我们推测BBA71是在哺乳动物感染过程中表达的一种表面暴露的外膜蛋白，它将在壁虎鼠感染伯氏杆菌时提供保护性免疫。我们将重点研究BBA71在哺乳动物感染的小鼠模型中扁虱和特定组织中的表达。我们将使用同源重组来删除BBA71在亲本B31菌株中的表达，以测试哺乳动物感染中对BBA71的绝对需求。最后，我们将评估BBA71被动和主动免疫对伯氏杆菌感染的保护作用。 莱姆病与全世界公共卫生的相关性越来越大，病例数量不断增加，诊断通常会出现延误。开发新的诊断和疫苗方法至关重要，这一提议为开发这些新疗法提供了机会，同时为候选人提供了理想的研究环境。匹兹堡大学和这里建议的指导支持为基础研究事业的发展提供了极好的工具。

DESCRIPTION (provided by applicant): The proposal describes a 5-year training program designed to provide the educational experiences and laboratory training for a successful career as an independent investigator in basic research in infectious diseases. The candidate has a long history of prior research activities, and this proposal includes formal coursework in biostatistics and study design that will complement the candidate's previous graduate work. The laboratory work will encompass areas of current competency and allow further training in immunohistochemistry, genetic manipulation of spirochetes, and animal models of infectious diseases. Dr. James Carroll, an expert in the area of experimental proteomics and molecular pathogenesis, will mentor the candidate, in close cooperation with an advisory committee of senior investigators from the institution. Lyme disease is the most common vector-borne infection reported in the United States, and has doubled in incidence in the past 10 years. Borrelia burgdorferi, the spirochete agent of Lyme disease, modulates its membrane proteins in the cycle of tick-mammal infection. We have observed that BBA71, a member of the pgf family of membrane proteins, is increased in expression at conditions which mimic mammalian infection. We hypothesize that BBA71 is a surface exposed outer membrane protein expressed during mammalian infection, which will provide protective immunity in tick-mouse infection with B. burgdorferi. We will focus early experiments on the expression of BBA71 in tick and specific tissues in the murine model of mammalian infection. We will be using homologous recombination to delete expression of BBA71 in the parent B31 strain to test the absolute requirement for BBA71 in mammalian infection. Finally, we will assess the protection from infection with B. burgdorferi conferred by passive and active immunization with BBA71. Lyme disease is of increasing relevance to public health worldwide with cases numbers mounting and diagnosis typically delayed. The development of new diagnostic and vaccine approaches is crucial, and this proposal gives the opportunity to develop these new therapies while providing an ideal research environment for the candidate. The University of Pittsburgh and the mentoring support proposed here offer excellent tools for the development of a career in basic research.