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

冈比亚 A. 含硫酯蛋白 1 (TEP1) 蛋白质-蛋白质相互作用

• 批准号: 8131148
• 负责人: Richard H. G. Baxter
• 金额: $ 10.8万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8131148
• 关键词: Actins; Adult; Affinity Chromatography; Africa South of the Sahara; Age; Anopheles Genus; Anopheles gambiae; Antibodies; Antimalarials; Arthropods; Bacterial Infections; Baculoviruses; Binding; Biological Assay; Biomedical Research; Blood Circulation; C-terminal; Cell Line; Cells; Cellular biology; Cessation of life; Chemicals; Chemistry; Chicago; Child; Chimeric Proteins; Collaborations; Complement; Complex; Conditioned Culture Media; Crystallization; Crystallography; Culicidae; Development; Disease; Doctor of Philosophy; Drosophila genus; Expression Library; Fellowships and Scholarships; France; Generations; Genetic; Genomics; Goals; Immune; Immune response; Immunity; Infection; Insecta; Insecticides; Institution; Intervention; Knowledge; Laboratories; Lead; Leucine; Malaria; Mediating; Medical center; Mentors; Methods; Molecular; Molecular Structure; Mycoses; Natural Immunity; Nobel Prize; Outcome; Parasites; Parasitic Diseases; Pathway interactions; Plasmodium; Plasmodium falciparum; Positioning Attribute; Protein Binding; Proteins; Proteomics; Recombinant Proteins; Recombinants; Research; Research Institute; Research Personnel; Set protein; Shuttle Vectors; Specialist; Structure; Surface; System; Texas; Training; Transfection; Ubiquitin; United States National Academy of Sciences; Universities; Virus; Work; authority; base; cDNA Library; complement pathway; disorder control; high throughput screening; in vivo; killings; leucine-rich repeat protein; medical specialties; member; novel; pathogen; programs; promoter; protein protein interaction; protein purification; protein structure; protein structure function; public health relevance; recombinant virus; research facility; response; skills; structural biology; thioester; vector; vector control

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.

描述（由申请人提供）：疟疾是世界上最具破坏性的寄生虫病，每年导致 100 万人死亡，其中大部分是撒哈拉以南非洲地区五岁以下的儿童。疟疾通过蚊子传播；因此，针对蚊子体内的疟疾（病媒控制）是控制这种疾病的核心。该项目涉及一种称为含硫酯蛋白 1 (TEP1) 的蛋白质，它是蚊子自身对疟疾感染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。该项目的成果应是 TEP1 在杀灭寄生虫方面发挥正常功能所必需的一组特定的蛋白质-蛋白质相互作用。然后可以通过遗传或药理学来操纵这些相互作用，以开发控制疟疾的新方法。例如，可能会开发出仅杀死感染疟疾的蚊子的新杀虫剂，甚至可以开发出增强蚊子对疟疾感染的免疫反应的化合物；有效治愈蚊子的疟疾。 这项研究由 Richard Baxter 博士进行，他是澳大利亚公民和美国永久居民，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。巴克斯特博士在研究生培训期间获得了奖学金和研究金支持，展示了他作为研究人员的独特技能和能力。 Baxter博士的博士学位属于化学领域，但他的研究涉及蛋白质的纯化和结晶，因此他既有严格的体能训练，又有适当的实验室技能，可以在分子水平上确定蛋白质的结构和功能。 Baxter 博士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，拥有 18 名著名的美国国家科学院院士和 4 名诺贝尔奖获得者，其中包括 Baxter 博士的导师、蛋白质晶体学领域的世界权威 Johann Deisenhofer 教授。 Baxter 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应将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结合起来。 Baxter 博士在获得美国学术机构的终身教授职位后，将继续与 Levashina 博士合作，在那里他将开发一个强大的研究计划，结合蛋白质组学、结构生物学和高通量筛选，以了解宿主免疫反应和宿主病原体相互作用对新出现和重新出现的节肢动物传播疾病的影响。 公共卫生相关性：含硫酯蛋白 1 (TEP1) 是蚊子对疟疾感染免疫反应的核心组成部分。要了解 TEP1 如何杀死疟疾寄生虫，必须对涉及 TEP1 的分子结构和蛋白质-蛋白质相互作用有基本了解。这些知识将导致控制和可能根除疟疾的新方法的发现。

项目成果

The structure and function of thioester-containing proteins in arthropods.

• DOI: 10.1007/s12551-014-0142-6
• 发表时间: 2014-12
• 期刊: Biophysical reviews
• 作者: Williams M;Baxter R
• 通讯作者: Baxter R

Biophysical analysis of anopheles gambiae leucine-rich repeat proteins APL1A1, APL1B [corrected] and APL1C and their interaction with LRIM1.

冈比亚按蚊富含亮氨酸的重复蛋白 APL1A1、APL1B [已校正] 和 APL1C 的生物物理分析及其与 LRIM1 的相互作用。

• DOI: 10.1371/journal.pone.0118911
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Williams,Marni;Summers,BradyJ;Baxter,RichardHG
• 通讯作者: Baxter,RichardHG