Functional genomic analysis of host determinants of malaria infection

疟疾感染宿主决定因素的功能基因组分析

• 批准号: 9171958
• 负责人: Elizabeth S. Egan
• 金额: $ 14.97万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9171958
• 关键词: 5 year old; Advisory Committees; Antimalarials; Area; Award; Biochemical; Bioinformatics; Biology; Boston; Candidate Disease Gene; Cells; Cessation of life; Child; Childhood; Clinical; Communicable Diseases; Data; Development; Development Plans; Discipline; Disease; Drug resistance; Effectiveness; Environment; Erythrocytes; Erythroid; Faculty; Falciparum Malaria; Flow Cytometry; Foundations; Funding; GCLC gene; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Population Study; Genetic Screening; Glutamate-Cysteine Ligase; Goals; Growth; Growth and Development function; Hematology; Human; Image; In Vitro; Individual; Infection; Institutes; Integration Host Factors; Invaded; Knowledge; Lentivirus; Longitudinal Studies; Malaria; Mediating; Medical; Mentorship; Microbiology; Molecular; Morbidity - disease rate; Parasites; Parasitology; Pathogenesis; Pediatric Hospitals; Phase; Phenocopy; Phenotype; Physicians; Plasmodium falciparum; Population Genetics; Positioning Attribute; Process; Properdin; Proteins; Proteome; Public Health Schools; RNA Interference; Research; Research Proposals; Resistance development; Resources; Role; Scientist; Secure; Senior Scientist; Severities; Staging; Surface; Symptoms; System; Testing; Therapeutic; Time; Training; Tropical Medicine; Validation; Work; base; career; career development; combat; design; functional genomics; genetic manipulation; human stem cells; inhibitor/antagonist; mortality; mutant; pathogen; pediatric department; progenitor; receptor; small molecule; stem cells; symposium; therapeutic target

DESCRIPTION (provided by applicant): Malaria is one of the leading causes of childhood mortality globally, responsible for the deaths of hundreds of thousands of children per year. While antimalarial drugs are widely available in endemic areas, their utility is compromised by the rapid development of drug resistance by Plasmodium falciparum parasites. All of the clinical symptoms of malaria are attributable to the stage of infection when parasites reside within erythrocytes. Since these cells are enucleated, they represent an attractive target for host-directed therapeutics, as they may be less likely to develop resistance. Population genetic studies support the idea that host factors can modulate the severity of malaria infections, but we have limited knowledge of the identity of such factors. We have designed an RNAi-based genetic screen to discover host factors required for invasion or growth of P. falciparum in erythrocytes. Our primary screen has identified ~10% of the erythrocyte proteome as candidates that may influence malaria pathogenesis. The overall goals of this proposal are to perform validation and functional studies on two of the most promising candidate host factors identified in the primary screen, as well as to perform secondary screens to validate and characterize the other candidates in a medium-throughput fashion. Along with the proposed research, the candidate's career development goals are to develop expertise in host-pathogen interactions in infectious diseases, molecular parasitology and erythrocyte genetics. These goals will be achieved by taking formal courses in Parasitology, Tropical Medicine, and Bioinformatics, as well as by attending Hematology and Parasitology seminars and conferences. She will receive direct mentorship from senior scientists in Parasitology, and will develop expertise in erythrocyte biology and genetics by collaborating with experts in the Hematology and functional genomics fields. In addition, the candidate will benefit from interactions with her Scientific Advisory Committee, which is composed of established scientists and physician-scientists from several disciplines, including Parasitology, Hematology, and Microbiology. The candidate's long-term career goals are to obtain a faculty position in academic medical department of Pediatric Infectious Diseases and to secure independent funding in order to continue her research on the host-pathogen interactions in malaria. The Harvard School of Public Health, Boston Children's Hospital, and The Broad Institute offer a rich training environment with all of the resources necessary to complete the proposed research. Boston Children's Hospital is committed to the candidate's career development plan and have assured that the candidate will have more than 80% protected time for the proposed research during the award period.

描述（由申请人提供）：疟疾是全球儿童死亡率的主要原因之一，导致每年数十万儿童死亡。虽然抗疟药在地方性地区广泛使用，但由于恶性疟原虫寄生虫迅速发展耐药性，它们的效用受到了损害。当寄生虫位于红细胞内时，疟疾的所有临床症状都归因于感染阶段。由于这些细胞被摘除，因此它们代表了宿主定向治疗剂的有吸引力的靶标，因为它们可能不太可能产生耐药性。人口遗传学研究支持这样一种观念，即宿主因素可以调节疟疾感染的严重程度，但我们对此类因素的身份有限。我们设计了一个基于RNAi的遗传筛选，以发现红细胞中恶性疟原虫侵袭或生长所需的宿主因素。我们的主要屏幕已将约10％的红细胞蛋白质组确定为可能影响疟疾发病机理的候选者。该提案的总体目标是对主要屏幕中确定的两个最有前途的候选宿主因素进行验证和功能研究，并执行辅助屏幕，以验证和以中等范围的方式来验证和表征其他候选者。除了拟议的研究外，候选人的职业发展目标是在传染病，分子寄生虫学和红细胞遗传学方面发展宿主病原体相互作用方面的专业知识。这些目标将通过参加寄生虫学，热带医学和生物信息学以及参加血液学和寄生虫学研讨会和会议的正式课程来实现这些目标。她将获得寄生虫学高级科学家的直接指导，并通过与血液学和功能基因组学领域的专家合作来发展红细胞生物学和遗传学方面的专业知识。此外，候选人将受益于与她的科学咨询委员会的互动，该委员会由来自多个学科的既定科学家和医师科学家组成，包括寄生虫学，血液学和微生物学。候选人的长期职业目标是在小儿传染病学术医学系中获得教职员工的职位，并获得独立的资金，以便继续研究疟疾的宿主病原体相互作用。哈佛大学公共卫生学院，波士顿儿童医院和广大研究所提供了丰富的培训环境，并提供了完成拟议研究所需的所有资源。波士顿儿童医院致力于候选人的职业发展计划，并保证候选人将在奖励期内有80％以上的保护时间。