Integrated genomics research in parasitic tropical diseases

热带寄生虫病的综合基因组学研究

基本信息

批准号：
9248256
负责人：
Joana Carneiro da Silva
金额：
$ 81.47万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9248256
关键词：
Adult Advanced Development Animal Model Animals Antimalarials Area Artemisinins Biology Blood Brugia Brugia malayi Cambodia Cellular Immunity Cessation of life Child Clinical Communicable Diseases Containment Data Development Diet Disease Disease Outcome Doxycycline Drug Targeting Drug resistance Epidemiology Falciparum Malaria Filarial Elephantiases Filariasis Funding Generations Genes Genetic Genetic Variation Genome Genomics Geography Goals Haplotypes Helminths Human Immune Immune response Immune system Immunity Immunologics In Vitro Infection Jird Laboratories Malaria Malaria Vaccines Malaria prevention Malnutrition Measurable Measures Mediating Metabolic MicroRNAs Micronutrients Molecular Nematoda Nematode infections Parasites Parasitic Diseases Pattern Phenotype Plasmodium Plasmodium falciparum Population Predisposition Preparation Prevalence Prevention Public Health RNA Interference Research Research Priority Resistance Sampling Science Seasons Site Southeastern Asia Specimen Sporozoite vaccine Techniques Technology Testing Time Tropical Disease Vaccine Antigen Vaccines Vitamin A Vitamin B Complex Whole Organism Wolbachia Work acquired immunity alternative treatment burden of illness disability drug candidate drug discovery endosymbiont epidemiology study experimental study field study fundamental research genome-wide genomic epidemiology genomic variation gut microbiome high throughput technology improved metabolome microbiome neglected tropical diseases new therapeutic target novel novel strategies nutrition parasite genome pathogen response sequencing platform statistics subcutaneous surveillance strategy tool transcriptome transcriptomics vaccine candidate vaccine development vaccine efficacy whole genome zinc finger nuclease

项目摘要

Parasitic diseases impose a tremendous toll on the global public health. Malaria causes up to 1.24 million deaths every year, while human filariasis remains a major cause of disability in the developing world. We propose to focus on two of the most important causative agents of parasitic disease in the world, the apicomplexan blood parasite Plasmodium falciparum, and the filarial nematode Brugia malayi, which causes lymphatic filariasis. We hypothesize that genomic variation in natural parasite populations and measurable interactions between host, parasites, and the microbiome can be exploited to develop novel strategies for control, treatment, and prevention of malaria and filariasis. The recent emergence and possible spread of artemisinin-resistant falciparum malaria in Southeast Asia threatens to derail malaria elimination efforts, and extensive genetic variation in natural populations of P. falciparum poses a major obstacle to the development of highly efficacious malaria vaccines. To provide new tools for surveillance and containment of drugresistant malaria, we will investigate the genetic basis of reduced susceptibility of P. falciparum to artemisinin antimalarial drugs. We will also identify loci in host and parasite genomes associated with protective naturally acquired immunity to P. falciparum in an effort to establish immune correlates of protection that can inform vaccine development. The characterization of genetic variation in parasite populations at sites where a whole organism vaccine will be tested represents a needed step toward the development of a broadly efficacious malaria vaccine. A new third generation long read sequencing platform will be applied for the first time to sequence and assemble malaria genomes using isolates collected in separately funded field studies. For filariasis, doxycycline is a promising new treatment that can target the adult worms, but more treatment alternatives are needed. We will identify novel filarial drug targets using genome and transcriptome data and examine their functionality and essentiality with RNAi. Because malnutrition is often co-endemic with filariasis, we will also examine the metabolic, transcriptomic, and microbiome response of infected animals kept on micronutrient deficient diets. Genomics, epidemiology, and fundamental research will be integrated in all of these endeavors to improve our understanding of the determinants of disease outcomes and facilitate the development of new tools for the control and elimination of malaria and filariasis.

寄生虫病给全球公共卫生造成巨大损失。疟疾导致多达 124 万人死亡每年都有人死亡，而人类丝虫病仍然是发展中国家残疾的主要原因。我们建议重点关注世界上两种最重要的寄生虫病病原体：顶复门血液寄生虫恶性疟原虫和丝虫线虫马来丝虫，其引起淋巴丝虫病。我们假设自然寄生虫种群中的基因组变异和可测量的可以利用宿主、寄生虫和微生物组之间的相互作用来开发新的策略控制、治疗和预防疟疾和丝虫病。最近的出现和可能的传播东南亚的青蒿素抗药性恶性疟疾可能会破坏消除疟疾的努力，并且恶性疟原虫自然群体中广泛的遗传变异对恶性疟原虫的发展构成了主要障碍高效的疟疾疫苗。为监测和遏制耐药性提供新工具疟疾，我们将研究恶性疟原虫对青蒿素敏感性降低的遗传基础抗疟药。我们还将确定宿主和寄生虫基因组中与自然保护相关的位点获得对恶性疟原虫的免疫力，努力建立保护的免疫相关性，从而可以提供信息疫苗开发。整个寄生虫种群的遗传变异特征将测试生物疫苗是开发广泛有效的疫苗所必需的一步疟疾疫苗。首次应用全新第三代长读长测序平台使用单独资助的实地研究中收集的分离株对疟疾基因组进行测序和组装。为了丝虫病，多西环素是一种有前途的新疗法，可以针对成虫，但治疗方法更多需要替代方案。我们将利用基因组和转录组数据确定新型丝虫药物靶标用 RNAi 检查它们的功能和必要性。因为营养不良常常与丝虫病，我们还将检查受感染动物的代谢、转录组和微生物组反应保持缺乏微量营养素的饮食。基因组学、流行病学和基础研究将整合在所有这些努力中，我们致力于提高我们对疾病结果决定因素的理解，促进开发控制和消除疟疾和丝虫病的新工具。