Genome wide assessment of essential genes in Trypanosoma brucei

布氏锥虫必需基因的全基因组评估

• 批准号: 8204844
• 负责人: KENNETH D STUART
• 金额: $ 83.29万
• 依托单位: SEATTLE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204844
• 关键词: Academia; Affinity Chromatography; African; African Trypanosomiasis; Allergic Disease; Applied Research; Basic Science; Biochemistry; Biological Assay; Biology; Blood; Blood Circulation; Categories; Cellular Morphology; Characteristics; Clinical Trials; Cloning; Communicable Diseases; Communities; Computer Simulation; Data; Databases; Development; Discipline; Disclosure; Disease; Drug Delivery Systems; Drug Kinetics; Drug resistance; Enzymes; Escherichia coli; Essential Genes; Evaluation; Flow Cytometry; Gene Expression; Genes; Genome; Genomics; Germ; Goals; Growth; Human; Immune System Diseases; In Vitro; Industry; Infection; Informatics; International; Knowledge; Lead; Leishmania; Libraries; Metabolism; Microscopy; Molecular and Cellular Biology; Mus; National Institute of Allergy and Infectious Disease; Output; Parasites; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plasmids; Preparation; Prevention program; Production; Proteins; RNA; RNA Interference; RNA analysis; Reagent; Recombinant Proteins; Research; Resources; Screening procedure; Set protein; Surveys; System; Technology; Testing; Time; Toxic effect; Toxicology; Transfection; Translating; Trypanosoma; Trypanosoma brucei brucei; Trypanosoma cruzi; Update; Validation; Wheat; assay development; base; cell growth; cost; drug candidate; drug development; drug discovery; genetic manipulation; genome sequencing; genome-wide; high throughput screening; in vivo; interest; knock-down; knowledge base; mouse model; novel; pathogen; programs; protein B; protein expression; protein structure; public health relevance; stable cell line; treatment program; vector; web site

DESCRIPTION (provided by applicant): Trypanosoma brucei, a WHO category one pathogen (emerging and uncontrolled), causes human African trypanosomiasis (HAT, aka African Sleeping Sickness), which is invariably fatal unless treated. New drugs are badly needed since current therapy is limited by toxicity, difficulty of administration, and spreading drug resistance. A wealth of knowledge has accumulated over the last 20-30 years on the molecular and cellular biology of T. brucei through a variety of hypothesis driven research programs. While several validated drug targets have arisen as a spin-off of these studies, there has been no systematic comprehensive effort to exploit the output of the genome projects and the recent advances in genetic manipulation of T. brucei to specifically identify and assess potential of drug targets. In addition, significant resources have been invested in setting up drug discovery programs including the building of facilities for high throughput screening (HTS) in several academic centers around the world. However, despite these efforts the list of validated drug targets that are both essential and likely to be "druggable" is small, and thus there are not enough high value targets that justify the considerable effort and resource of a HTS, or a dedicated drug discovery effort. This proposal is part of a coordinated effort by our US-based group (Stuart and Phillips) and our collaborators in the UK (Drs. M. Fergusson and J. Mottram), to undertake RNAi (interfering RNA) analysis in a genome-wide survey for essential, and "druggable" targets in T. brucei. A genome-wide data-base that lists key data required for target assessment in drug discovery is being compiled by the WHO/TDR and will be a key resource for target selection. While this proposal focuses on HAT, genetically validated targets in T. brucei may translate to T. cruzi and Leishmania species, and thus these studies will provide a resource for the entire kinetoplastid community. All data generated from the project will be provided to the tdrtargets.org curators for public distribution on that web site. The goals of this three year study are to 1) Select 200 - 300 genes in the T. brucei genome for RNAi essentiality analysis based on an assessment of potential "druggability"; 2) to determine if the selected genes are essential for the growth of blood form T. brucei parasites in vitro and in vivo by RNAi analysis; 3) to develop high-yield heterologous protein expression systems and suitable enzyme assays for genes that are shown to be essential; and 4) to organize data and reagents to provide distribution to the T. brucei research community. PUBLIC HEALTH RELEVANCE: The goal of the National Institute of Allergy and Infectious Diseases (NIAID) is to support basic and applied research leading to a better understanding of infectious, immunologic, and allergic diseases with the goal of generating new treatments or prevention programs for these diseases. The direct goal of this proposal is to identify new drug targets for the development of novel treatment programs against several priority trypanosomal pathogens that have been of long standing interest in the NIAID portfolio.

描述（由申请方提供）：布氏锥虫是一种世卫组织第一类病原体（新兴和不受控制），可引起人类非洲锥虫病（HAT，又名非洲昏睡病），除非治疗，否则总是致命的。由于目前的治疗受到毒性、给药困难和耐药性扩散的限制，因此迫切需要新的药物。在过去的20-30年里，对T.通过各种假设驱动的研究项目，虽然一些经过验证的药物靶点已经作为这些研究的副产品出现，但还没有系统的综合努力来利用基因组计划的输出和T.专门确定和评估药物靶点的潜力。此外，大量资源已投入建立药物发现计划，包括在世界各地的几个学术中心建设高通量筛选（HTS）设施。然而，尽管做出了这些努力，但既必要又可能是“可用药的”的经验证的药物靶标的列表很小，因此没有足够的高价值靶标来证明HTS或专门的药物发现努力的相当大的努力和资源是合理的。这项建议是我们美国小组（斯图尔特和菲利普斯）和我们在英国的合作者（M。Fergusson和J. Mottram），在T.布鲁塞。世界卫生组织/贸易和发展报告正在汇编一个全基因组数据库，其中列出了药物发现中目标评估所需的关键数据，该数据库将成为目标选择的关键资源。虽然这项建议的重点是HAT，遗传验证的目标在T。brucei可能翻译为T.因此，这些研究将为整个动质体群落提供资源。该项目产生的所有数据将提供给tdrtargets.org策展人，以便在该网站上公开分发。这项为期三年的研究的目标是：1）在T.基于潜在的“可药用性”的评估，用于RNAi必要性分析的布鲁氏菌基因组; 2）确定所选基因是否是T型血生长所必需的。通过RNAi分析在体外和体内研究布鲁氏菌寄生虫; 3）开发高产异源蛋白表达系统和用于显示为必需的基因的合适的酶测定;和4）组织数据和试剂以提供分布到T.布鲁斯研究社区。 公共卫生关系：国家过敏和传染病研究所（NIAID）的目标是支持基础和应用研究，以更好地了解传染病，免疫学和过敏性疾病，并为这些疾病制定新的治疗或预防方案。该提案的直接目标是确定新的药物靶点，以开发针对NIAID产品组合中长期感兴趣的几种优先锥虫病原体的新型治疗方案。

项目成果

GMP synthase is essential for viability and infectivity of Trypanosoma brucei despite a redundant purine salvage pathway.

• DOI: 10.1111/mmi.13083
• 发表时间: 2015-09
• 期刊: Molecular microbiology
• 影响因子: 3.6
• 作者: Li Q;Leija C;Rijo-Ferreira F;Chen J;Cestari I;Stuart K;Tu BP;Phillips MA
• 通讯作者: Phillips MA

An Antiparasitic Compound from the Medicines for Malaria Venture Pathogen Box Promotes Leishmania Tubulin Polymerization.

• DOI: 10.1021/acsinfecdis.0c00122
• 发表时间: 2020-08-14
• 期刊: ACS infectious diseases
• 影响因子: 5.3
• 作者: Ullah I;Gahalawat S;Booshehri LM;Niederstrasser H;Majumdar S;Leija C;Bradford JM;Hu B;Ready JM;Wetzel DM
• 通讯作者: Wetzel DM