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: 8666714
• 负责人: Elizabeth S. Egan
• 金额: $ 18.33万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8666714
• 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; Commit; 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; 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; Stem cells; Subfamily lentivirinae; 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; 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. PROJECT NARRATIVE: Plasmodium falciparum malaria is a significant cause of morbidity and mortality among children globally, responsible for over 600,000 deaths per year. Drug resistance hampers the effectiveness of parasite-directed antimalarial drugs currently in clinical use; an alternative approach is to target host proteins essential for malaria infection. Here, host proteins required for P. falciparum replication in erythrocytes will be identified using a genetic screen and characterized in terms of their roles in the host-parasite interaction. The results of this work will ultimately guide the rational development of host-targeted therapeutics for malaria.

描述（由申请人提供）：疟疾是全球儿童死亡的主要原因之一，每年导致数十万儿童死亡。虽然抗疟药物在流行地区广泛使用，但其效用因恶性疟原虫寄生虫耐药性的迅速发展而受到影响。疟疾的所有临床症状都可归因于寄生虫驻留在红细胞内的感染阶段。由于这些细胞被去核，它们代表了宿主导向治疗的一个有吸引力的靶标，因为它们不太可能产生耐药性。群体遗传学研究支持宿主因素可以调节疟疾感染严重程度的观点，但我们对这些因素的身份了解有限。我们设计了一种基于 RNAi 的遗传筛选，以发现恶性疟原虫在红细胞中入侵或生长所需的宿主因子。我们的初步筛选已确定约 10% 的红细胞蛋白质组为可能影响疟疾发病机制的候选者。该提案的总体目标是对初级筛选中确定的两个最有希望的候选宿主因子进行验证和功能研究，以及进行二级筛选以中等通量的方式验证和表征其他候选宿主因子。除了拟议的研究之外，候选人的职业发展目标是发展传染病、分子寄生虫学和红细胞遗传学中宿主与病原体相互作用的专业知识。这些目标将通过参加寄生虫学、热带医学和生物信息学的正式课程以及参加血液学和寄生虫学研讨会和会议来实现。她将接受寄生虫学资深科学家的直接指导，并将通过与血液学和功能基因组学领域的专家合作，发展红细胞生物学和遗传学方面的专业知识。此外，候选人还将受益于与她的科学咨询委员会的互动，该委员会由来自寄生虫学、血液学和微生物学等多个学科的知名科学家和医师科学家组成。该候选人的长期职业目标是在儿科传染病学术医学系获得教职，并获得独立资金，以继续她对疟疾宿主与病原体相互作用的研究。哈佛大学公共卫生学院、波士顿儿童医院和布罗德研究所提供了丰富的培训环境以及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，并保证候选人在获奖期间将有超过 80% 的受保护时间用于拟议的研究。 项目叙述：恶性疟原虫疟疾是全球儿童发病和死亡的一个重要原因，每年导致超过 600,000 人死亡。耐药性阻碍了目前临床使用的针对寄生虫的抗疟药物的有效性；另一种方法是针对疟疾感染所必需的宿主蛋白。来了，楼主 恶性疟原虫在红细胞中复制所需的蛋白质将通过遗传筛选进行鉴定，并根据它们在宿主-寄生虫相互作用中的作用进行表征。这项工作的结果将最终指导合理开发针对疟疾的宿主靶向疗法。