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的五岁以下儿童。疟疾通过蚊子传播；因此，以蚊子体内的疟疾为目标（媒介控制）是控制这种疾病的核心。这个项目涉及一种叫做含硫酯蛋白1 （TEP1）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TEP1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。这个项目的结果应该是一组特定的蛋白质-蛋白质相互作用，这是TEP1在寄生虫杀死中的正常功能所必需的。然后可以从基因或药理学上操纵这些相互作用，以开发控制疟疾的新方法。例如，可以开发只杀死感染疟疾的蚊子的新杀虫剂，甚至可以开发增强蚊子对疟疾感染免疫反应的化合物；有效地治愈了蚊子的疟疾。

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.