Molecular mechanisms of filarial endosymbiosis

描述（由申请方提供）：马来蠕虫是人类淋巴丝虫病（通常称为象皮病）的主要病原体，这是一种被忽视的热带疾病，是全球第二大致病原因。普遍用于控制这种痛苦、毁容和失能疾病的大规模药物管理计划由于潜在的耐药性而面临失败的风险。本项目的目标是定义 决定寄生线虫B. malayi及其基本细菌内共生体Wolbachia，以发现可以消除蠕虫的新治疗方法。已知线虫的生物学和其内共生体是相互依赖的，但这种关系的基础尚未阐明。使用抗生素消除寄生虫中的沃尔巴克氏体会影响蠕虫的蜕皮，繁殖和存活，这表明细菌对寄生虫的发育至关重要;因此，它们代表了控制感染的有吸引力的目标。我们打算在分子水平上研究寄生虫及其内共生体之间的相互作用，使用候选的Brugia-Wolbachia蛋白复合物和已被确定为内共生关系中的主要参与者的途径，并测试microRNA（miRNA）在调节相互作用中的作用。这种方法具有最大的潜力，以扩大我们对这一生物系统的知识，这是目前知之甚少。我们提出了一个独特的应用新技术，结合传统技术，产生的数据，将回答有关内共生关系的重要问题，并在这样做，提供开创性的信息沃尔巴克氏体研究领域的一般。我们的三个主要目标是：1）定义沃尔巴克氏体表面蛋白在内共生关系中的生理作用; 2）确定miRNA是否调节B。马来核基因表达的Wolbachia-Brugia关系;和3）特征的Wolbachia为B提供的基本功能。马来蜕皮

DESCRIPTION (provided by applicant): Brugia malayi worms are major causative agents of human lymphatic filariasis (more commonly known as elephantiasis), a neglected tropical disease that is the second leading cause of morbidity worldwide. The mass drug administration programs universally used to control this painful, disfiguring, and incapacitating disease are at risk of failure due to the potential for drug resistance. The goal of this project is to define the mechanisms that determine the interdependencies between the parasitic nematode B. malayi and its essential bacterial endosymbiont, Wolbachia, in order to discover novel means of treatment that can eliminate the adult worms. The biology of the nematode and its endosymbiont are known to be co-dependent, but the basis of this relationship has yet to be elucidated. Eliminating Wolbachia from the parasites using antibiotics affects molting, reproduction, and survival of the worms, indicating that the bacteria are crucial for the development of the parasite; thus, they represent an attractive target for control of the infections. We intend to study the interaction of the parasite and its endosymbiont at the molecular level using candidate Brugia-Wolbachia protein complexes and pathways that have been identified as major players in the endosymbiotic relationship, and test the role of microRNAs (miRNAs) in regulating interactions. This approach has the greatest potential to expand our knowledge of this biological system, which is currently poorly understood. We propose a unique application of new technologies, in combination with traditional techniques, to generate data that will answer important questions about the endosymbiotic relationship and, in so doing, provide groundbreaking information to the Wolbachia research field in general. Our three primary aims are to: 1) define the physiological role of Wolbachia surface proteins in the endosymbiotic relationship; 2) determine if miRNAs regulate B. malayi nuclear gene expression in the Wolbachia-Brugia relationship; and 3) characterize the essential functions provided by Wolbachia for B. malayi molting.