Regulation of glycerol utilization in Borrelia burgdorferi

项目摘要/摘要 莱姆病是由伯氏疏螺旋体感染引起的。B.burgdorferi被保存在 地方性循环中的自然界，包括壁虱媒介和脊椎动物宿主。螺旋体改变了它的来源 从脊椎动物中的葡萄糖到扁虱中的甘油的碳和能量：甘油的利用是至关重要的 适应螺旋体在硬体动物体内存活并成功传播给脊椎动物。我们假设 甘油代谢和糖酵解的界面，通过甘油-3-磷酸和甘油-3-磷酸的相互转化而联系在一起 磷酸二羟丙酮是地方病循环中的代谢关键。中心假说 这种应用的应用是伯氏杆菌转录后调节甘油代谢的表达 (GLP)操纵子利用甘油以在其扁虱载体中生存。我们努力剖析分子 调节GLP操纵子表达的机制，包括新的反义RNA和 环二聚体GMP(c-di-GMP)结合蛋白Plza。提出了以下具体目标 实现这一目标：1)确定在地方病流行期间参与甘油代谢的基因的作用 循环；2)确定GLP操纵子调控的分子机制；3)确定Plza和Plza的功能。 确定其在调节GLP操纵子中的作用。遗传、生化、分子和转录组 这些方法以及莱姆病的壁虱-老鼠模型将被用来进行实验测试。 假设。在这一创新应用中，多PI处于独特的体验地位， 专业知识和实验模型，以加强对碳水化合物新陈代谢的机理理解 以及在莱姆病病原体在其扁虱媒介中持续期间的调节。的长期目标是 这项建议是为了了解允许伯氏杆菌做出反应和适应的调节机制。 不同的碳源在扁虱到哺乳动物的传播和莱姆病的发病机制中，这将导致 改进诊断、预防和治疗策略，因为甘油和葡萄糖的利用 分别对扁虱和脊椎动物感染期间的持久性至关重要；这与 为了减轻人类疾病，该机构需要“寻求基础知识”。

PROJECT SUMMARY/ABSTRACT Lyme disease is caused by infection with the spirochete Borrelia burgdorferi. B. burgdorferi is maintained in nature in an enzootic cycle comprising a tick vector and vertebrate host. The spirochete shifts its source of carbon and energy from glucose in the vertebrate to glycerol in the tick: utilization of glycerol is a crucial adaptation for the spirochete to persist in the tick and successfully transmit to a vertebrate. We hypothesize that the interface of glycerol metabolism and glycolysis, linked by interconversion of glycerol-3-phosphate and dihydroxyacetone phosphate, is the metabolic linchpin for navigating the enzootic cycle. The central hypothesis of this application is that B. burgdorferi post-transcriptionally regulates expression of the glycerol metabolism (glp) operon to utilize glycerol in order to survive in its tick vector. We endeavor to dissect the molecular mechanisms regulating expression of the glp operon, including the specific roles of a novel antisense RNA and the cyclic-dimeric GMP (c-di-GMP)-binding protein PlzA. The following specific aims are proposed toward achieving this objective: 1) define the role of the genes involved in glycerol metabolism during the enzootic cycle; 2) determine the molecular mechanism of glp operon regulation; and 3) define the function of PlzA and determine its role in regulating the glp operon. Genetic, biochemical, molecular, and transcriptomic approaches, as well as the tick-mouse model of Lyme disease, will be utilized to experimentally test these hypotheses. In this innovative application, the Multiple-PIs are in the unique position of having the experience, expertise, and experimental models to enhance the mechanistic understanding of carbohydrate metabolism and its regulation during the persistence of the Lyme disease agent in its tick vector. The long-term objective of this proposal is to understand the regulatory mechanisms that allow B. burgdorferi to respond and adapt to varied carbon sources in the tick-to-mammal transmission and in Lyme disease pathogenesis, which will lead to improved diagnostic, prevention, and treatment strategies because glycerol and glucose utilization are critical for persistence during tick and vertebrate infection, respectively; this is relevant to the mission of the agency to “seek fundamental knowledge” for the sake of alleviating human disease.