A. gambiae thioester-containing protein 1 (TEP1) protein-protein interactions

描述（由申请人提供）：疟疾是世界上最具破坏性的寄生虫病，每年造成100万人死亡，其中大多数是撒哈拉以南非洲5岁以下的儿童。疟疾通过蚊子传播;因此，针对蚊子体内的疟疾（病媒控制）是控制这一疾病的核心。该项目涉及一种名为含硫酯蛋白1（TEP 1）的蛋白质，它是蚊子自身对疟疾感染的免疫反应的主要因素。目的是鉴定与TEP 1相互作用的其他蚊子蛋白，并在分子水平上表征这些相互作用。本项目的成果将是一组特定的蛋白质-蛋白质相互作用，这是TEP 1在杀死寄生虫中的适当功能所必需的。这些相互作用可以通过基因或生物学手段加以操纵，从而开发出控制疟疾的新方法。例如，可能会开发出只杀死感染疟疾的蚊子的新杀虫剂，甚至是增加蚊子对疟疾感染的免疫反应的化合物;实际上治愈了疟疾蚊子。 本研究应由澳大利亚公民和美国永久居民Richard巴克斯特博士进行，他自1998年开始攻读博士学位以来一直居住在美国。在芝加哥大学。巴克斯特博士在整个研究生培训期间获得奖学金和研究金支持，证明了他作为研究人员的独特技能和能力。巴克斯特博士的博士学位是在化学领域，但他的研究涉及蛋白质的纯化和结晶，因此他既有严格的物理训练和适当的实验室技能，以确定蛋白质的结构和功能在分子水平。 博士巴克斯特的研究最初将在德克萨斯大学西南医学中心进行，该中心是美国首屈一指的生物医学研究机构之一。UT Southwestern拥有世界一流的研究设施，着名的国家科学院的18名成员和4名诺贝尔奖获得者，其中包括巴克斯特博士的导师Johann Deisenhofer教授，他是蛋白质晶体学领域的世界权威。巴克斯特博士的研究将与法国斯特拉斯堡大学的Elena Levashina博士合作进行，Elena Levashina博士是蚊子对疟疾免疫反应的专家，在国际公认的昆虫免疫领域先驱Jules Hoffmann教授的指导下进行。这两个实验室之间的合作将联合收割机在蛋白质纯化和结构测定方面的互补专业与体内细胞生物学研究相结合。 博士巴克斯特在获得美国学术机构的终身职位后，应继续与Levashina博士合作，在该学术机构中，他应制定一项强大的研究计划，包括蛋白质组学、结构生物学和高通量筛选，以了解与新发和再发节肢动物传播疾病有关的宿主免疫反应和宿主-病原体相互作用。 含硫酯蛋白1（TEP 1）是蚊子对疟疾感染的免疫反应的核心成分。对涉及TEP 1的分子结构和蛋白质-蛋白质相互作用的基本理解对于了解它如何杀死疟疾寄生虫是必要的。这些知识将导致发现控制和可能根除疟疾的新方法。

DESCRIPTION (provided by applicant): Malaria is the world's most devastating parasitic disease, killing 1 million people per year, mostly children under the age of five in sub-Saharan Africa. Malaria is transmitted through mosquitoes; hence targeting malaria within mosquitoes (vector control) is central to controlling this disease. This project concerns a protein called thioester-containing protein 1 (TEP1) that is the major factor in the mosquitoes own immune response to malaria infection. The aim is to identify other mosquito proteins that interact with TEP1 and characterize those interactions at the molecular level. The outcome of this project shall be a specific set of protein- protein interactions that are necessary for the proper function of TEP1 in parasite killing. These interactions can then be manipulated either genetically or pharmacologically to develop new methods for malaria control. For instance new insecticides may be developed that kill only mosquitoes infected with malaria, or even compounds that increase the immune response of mosquitoes to malaria infection; in effect curing mosquitoes of malaria. This research shall be conducted by Dr. Richard Baxter, an Australian citizen and US permanent resident, who has resided in the US since 1998 when he commenced his Ph.D. at the University of Chicago. Dr. Baxter received scholarship and fellowship support throughout his graduate training, demonstrating his unique skills and abilities as a researcher. Dr. Baxter's doctoral degree is in the field of chemistry, but his research involves the purification and crystallization of proteins, therefore he has both the rigorous physical training and the appropriate laboratory skills to determine the structure and function of proteins at the molecular level. Dr. Baxter's research shall initially be conducted at University of Texas Southwestern Medical Center, one of the premier biomedical research institutes in the nation. UT Southwestern boasts world-class research facilities, 18 members of the prestigious National Academy of Sciences and four Nobel Prize winners, including Dr. Baxter's mentor Prof. Johann Deisenhofer, a world authority in the field of protein crystallography. Dr. Baxter's research shall be performed in collaboration with Dr. Elena Levashina at the University of Strasbourg, France, a specialist in the immune response of mosquitoes to malaria, under Prof. Jules Hoffmann, an internationally recognized pioneer in the field of insect immunity. The collaboration between these two laboratories shall combine complementary specialties in protein purification and structure determination with cell biology studies in vivo. Dr. Baxter shall continue his collaboration with Dr. Levashina upon obtaining a tenure-track position at a US academic institution, where he shall develop a robust research program incorporating proteomics, structural biology and high throughput screening to understand host immune responses and host-pathogen interactions bearing on emergent and re-emergent arthropod-borne diseases. PUBLIC HEALTH RELEVANCE: Thioester-containing protein 1 (TEP1) is a central component of the immune response of mosquitoes to malaria infection. A fundamental understanding of molecular structure and protein-protein interactions involving TEP1 are necessary to understand how it kills malaria parasites. This knowledge shall then lead to the discovery of new ways to control and possibly eradicate malaria.