Unique functions of the mitochondrial tRNA import machinety in T. gondii

弓形虫线粒体 tRNA 输入机制的独特功能

基本信息

批准号：
8425182
负责人：
Lilach Sheiner
金额：
$ 9万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8425182
关键词：
Address Affinity Chromatography Amino Acyl Transfer RNA Animal Model Apicomplexa Biochemical Biogenesis Bioinformatics Biological Biological Process Biology Biomedical Research Bypass Candidate Disease Gene Cell Line Core Facility Data Defect Development Drug Targeting Electron Transport Engineering Environment Essential Genes Faculty Falciparum Malaria Fostering Foundations Gene Pool Generations Genes Goals HIV Hand Homologous Gene Human Immunocompromised Host Individual Infection Institution Intervention Kinetoplastida Malaria Measures Membrane Potentials Mentors Messenger RNA Methods Mitochondria Mitochondrial Proteins Modeling Molecular Names Organ Transplantation Organelles Organism Parasites Pathway interactions Patients Pattern Pharmaceutical Preparations Phase Phylogenetic Analysis Plasmodium Plastids Post-Translational Protein Processing Postdoctoral Fellow Poverty Preparation Process Protein Import Proteins Protocols documentation Publishing Reagent Relative (related person)Research Research Design Research Personnel Role Scientist Source System Toxoplasma Toxoplasma gondii Toxoplasmosis Transfer RNA Transgenic Organisms Translations Transplant Recipients Trypanosoma brucei brucei Vaccines Work base biodefense career congenital infection design experience genetic manipulation insight interest malarone member method development mortality mutant neglect novel positional cloning post-doctoral training public health relevance skills tool

项目摘要

DESCRIPTION (provided by applicant): The applicant, Lilach Sheiner, is highly accomplished in Toxoplasma gondii genetic manipulation, and has recently developed a pipeline to identify and characterize genes encoding unique components of parasite endosymbiotic organelles. During the mentored phase, the applicant will utilize this system and focus on the identification and disruption of parasite-specific components of mitochondrial tRNA import (MITI) that are likely suitable as new drug targets. Furthermore the candidate will develop tools to characterize the biological function of MITI components, and will master the relevant biochemical skills, with the help of the mentors. As an independent investigator at an institution of basic biomedical research, she will apply these molecular and biochemical tools to study MITI and other parasite-specific aspects of mitochondrial biogenesis, as a promising source for drug targets. The CTEGD fosters a highly collaborative research environment with 19 faculty members interested in various aspects of parasite biology and with excellent core facilities. The mentor, Boris Striepen, is an expert on endosymbiont biology in T. gondii and is one of the leading scientists in the field of molecular research in these parasites. The co-mentor, Stephen Hajduk, is an expert biochemist with wide ranging experience in parasite mitochondria biogenesis, and who has specific interest in MITI in parasites. The T. gondii mitochondrion is essential and shows several unique features. Recent data suggests that MITI in these parasites is likely to be dependent on a divergent machinery. The goal of this proposal is to identify the components responsible for this divergence, utilizing a novel bioinformatics search strategy, and to address their function by reverse genetics, using a new streamlined system to generate conditional mutants. While some tools to characterize tRNA import and mitochondrial function in T. gondii are at hand, others await development and adaptation. Isolation of pure mitochondria has not been established, which limits the extent of biochemical research available. This challenge will be addressed in the proposed project. These studies will open new perspectives on the biogenesis of the T. gondii mitochondrion and hence contribute to the design of new countermeasures, also of relevance to other apicomplexan parasites such as the causative agent of malaria, Plasmodium falciparum.

描述（由申请人提供）：申请人 Lilach Sheiner 在弓形虫基因操作方面具有很高的造诣，最近开发了一种管道来识别和表征编码寄生虫内共生细胞器的独特成分的基因。在指导阶段，申请人将利用该系统，重点鉴定和破坏可能适合作为新药物靶点的线粒体 tRNA 输入 (MITI) 的寄生虫特异性成分。此外，候选人将开发工具来表征 MITI 成分的生物学功能，并在导师的帮助下掌握相关的生化技能。作为基础生物医学研究机构的独立研究员，她将应用这些分子和生化工具来研究 MITI 和线粒体生物发生的其他寄生虫特异性方面，作为药物靶标的有前途的来源。 CTEGD 营造了一个高度协作的研究环境，拥有 19 名对寄生虫生物学各个方面感兴趣的教员，并拥有卓越的核心设施。导师鲍里斯·斯特里彭 (Boris Striepen) 是弓形虫内共生生物学专家，也是这些寄生虫分子研究领域的领先科学家之一。共同导师 Stephen Hajduk 是一位生物化学专家，在寄生虫线粒体生物发生方面拥有丰富的经验，并且对寄生虫中的 MITI 特别感兴趣。弓形虫线粒体是必不可少的，并显示出一些独特的特征。最近的数据表明，这些寄生虫中的 MITI 可能依赖于不同的机制。该提案的目标是利用一种新颖的生物信息学搜索策略来识别造成这种分歧的成分，并通过反向遗传学来解决它们的功能，使用一种新的简化系统来生成条件突变体。虽然一些表征弓形虫 tRNA 输入和线粒体功能的工具已经存在，但其他工具仍在等待开发和适应。纯线粒体的分离尚未建立，这限制了可用的生化研究的范围。这一挑战将在拟议的项目中得到解决。这些研究将为弓形虫线粒体的生物发生开辟新的视角，从而有助于设计新的对策，也与其他顶复门寄生虫（例如疟疾的病原体恶性疟原虫）相关。