The Role of BBI36/38 in Lyme Disease Pathogenesis

BBI36/38 在莱姆病发病机制中的作用

基本信息

批准号：
8129243
负责人：
ANDREW J NOWALK
金额：
$ 5万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8129243
关键词：
Active Immunization Advisory Committees Animal Model Animals Antibodies Area Arthritis Bacteria Bacteria sigma factor KatF protein Basic Science Biometry Blood Borrelia Borrelia burgdorferi C3H/HeJ Mouse Carditis Cells Chickens Clinical Communicable Diseases Complement Complex Data Development Diagnosis Digestion Effectiveness Environment Exposure to Family Gene Family Genes Growth Heart Human Humoral Immunities Immune Sera Immunity Immunization Immunohistochemistry In Vitro Incidence Individual Infection Institution Investigation Ixodes Joints Knock-out Laboratories Life Cycle Stages Lipoproteins Lyme Disease Mammals Marketing Membrane Membrane Proteins Mentors Midgut Modeling Molecular Mus Needles North America Order Spirochaetales Organ OspA protein Parents Passive Immunization Pathogenesis Pathology Pattern Plasmids Play Proteins Proteome Proteomics Public Health RNA Reagent Recombinants Recording of previous events Regulation Reporting Research Research Activity Research Design Research Personnel Reverse Transcriptase Polymerase Chain Reaction Role Salivary Glands Serological Serum Simulate Site Skin Specificity Staging Stimulus Surface Symptoms Temperature Testing Ticks Time Tissue-Specific Gene Expression Tissues Training Training Programs United States Universities Vaccines Withdrawal Work base career cross reactivity design experience feeding genetic manipulation homologous recombination immunogenic lyme vaccine maltose-binding protein member mouse model mutant novel diagnostics overexpression paralogous gene programs promoter protein B protein expression research study response tissue tropism tool development transmission process vector

项目摘要

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.

描述（由申请人提供）：该提案描述了一个为期 5 年的培训计划，旨在为传染病基础研究的独立研究者提供成功职业生涯的教育经验和实验室培训。候选人之前有长期的研究活动历史，该提案包括生物统计学和研究设计方面的正式课程，这将补充候选人之前的研究生工作。实验室工作将涵盖当前能力领域，并允许在免疫组织化学、螺旋体基因操作和传染病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高级研究人员咨询委员会密切合作，为候选人提供指导。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，在蜱哺乳动物感染周期中调节其膜蛋白。我们观察到，BBA71（膜蛋白 pgf 家族的成员）在模拟哺乳动物感染的条件下表达增加。我们假设 BBA71 是哺乳动物感染期间表达的表面暴露的外膜蛋白，它将在蜱鼠感染伯氏疏螺旋体时提供保护性免疫。我们将早期实验的重点放在哺乳动物感染的鼠模型中蜱和特定组织中 BBA71 的表达。我们将使用同源重组来删除亲本 B31 菌株中 BBA71 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疏螺旋体感染的保护作用。莱姆病与全球公共卫生的关系日益密切，病例数量不断增加，诊断通常会延迟。新的诊断和疫苗方法的开发至关重要，该提案提供了开发这些新疗法的机会，同时为候选人提供了理想的研究环境。匹兹堡大学和这里提出的指导支持为基础研究职业的发展提供了极好的工具。