MOLECULAR ANALYSIS OF MALARIA MITOCHONDRIAL GENE REGULATION

疟疾线粒体基因调控的分子分析

• 批准号: 10294685
• 负责人: Kristin D Lane
• 金额: $ 35.13万
• 依托单位: IDAHO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10294685
• 关键词: Address; Alleles; Biochemistry; Biological Assay; Biology; Biotin; Cell physiology; Circular DNA; Complex; Crista ampullaris; DNA; DNA Repair Pathway; DNA-Directed RNA Polymerase; Data; Development; Drug Design; Drug Targeting; Drug resistance; Electron Transport; Engineering; Enzymes; Eukaryota; Evolution; Exonuclease; Exposure to; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Recombination; Genetic Transcription; Genome; Goals; Histones; Human; In Vitro; Knowledge; Label; Laboratories; Life; Link; Malaria; Metabolic; Methods; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins; Mitochondrial RNA; Modeling; Molecular Analysis; Mutate; Mutation; Organelles; Parasites; Pathway interactions; Peptide Initiation Factors; Plasmodium falciparum; Preparation; Process; Proteome; Regulation; Regulatory Pathway; Repression; Resistance; Sequence Analysis; Sigma Factor; Source; System; Techniques; Translations; drug development; falls; genome sequencing; in vivo; inhibitor; member; mitochondrial genome; mutant; new therapeutic target; novel; novel strategies; novel therapeutics; pressure; protein complex; reconstitution; targeted treatment; transcriptome; treatment strategy; whole genome

The human malaria parasite, Plasmodium falciparum, rapidly evolves drug resistance, creating the urgent need for new treatment strategies. A critical barrier to identifying and developing new drug development targets is a knowledge gap regarding most essential processes and regulatory pathways. Ideally, new targets should be highly conserved and be unable or have limited ability to mutate in order to evolve resistance. Parasite mitochondrial function is critically essential across all the life stages and differs substantially from the human organelle; however, most mitochondrial proteins have yet to be identified in malaria parasites. During the intraerythrocytic development cycle (IDC), P. falciparum is supported by a single mitochondrion containing about ~20 copies of the 6 kb genome, characterized by extensive recombination. IDC parasite mitochondria do not make cristae to insert electron transport chain (ETC) enzymes, thus the organelle may have evolved unique transcription or translation repression systems to limit expression of the mitochondrial encoded genes. Results from our integrative approach combining whole genome sequencing and metabolic profiling, suggests a link between mitochondrial gene expression regulation and resistance to ETC inhibitors, potentially due to recombination. Thus, we hypothesize that 1) a feature of the multicopy status is retention of cryptic mitochondrial genome copies encoding mutant alleles, which can be recombined for survival. 2) P. falciparum mitochondria use previously uncharacterized gene expression systems, for repression and activation which are unique to this organelle. The current objectives are to identify the source of recombination between mitochondrial genomes and its contribution to drug resistance as well as to determine the mitochondrial DNA repair pathways and transcriptional machinery of the mitochondria using single-organelle approaches. This proposal will identify and define previously unknown and uncharacterized aspects of parasite biology, with the goal of advancing rational drug design. These studies will refine our knowledge about the basic mechanism of gene regulation in the malaria mitochondria. Investigating the mechanisms underpinning these effects will lead to the identification of highly conserved drug development targets.

人类疟疾寄生虫，恶性疟原虫，迅速进化出抗药性， 迫切需要新的治疗策略。识别和开发新的 药物开发目标是关于最基本过程和监管的知识差距 路径。理想情况下，新靶标应该是高度保守的，并且不能或具有有限的能力， 变异以进化出抵抗力寄生虫的线粒体功能至关重要 在所有的生命阶段，并与人类细胞器有很大的不同;然而，大多数 在疟疾寄生虫中还有待鉴定线粒体蛋白。在红细胞内 在发育周期（IDC）中，恶性疟原虫由含有约 ~20个拷贝的6 kb基因组，以广泛重组为特征。IDC寄生虫 线粒体不使嵴插入电子传递链（ETC）酶，因此， 细胞器可能进化出独特的转录或翻译抑制系统， 线粒体编码基因的表达。我们的综合方法结合了 全基因组测序和代谢分析，表明线粒体基因之间的联系， 表达调控和对ETC抑制剂的抗性，可能是由于重组。因此，在本发明中， 我们假设：1）多拷贝状态的一个特征是隐藏的线粒体 编码突变等位基因的基因组拷贝，其可以重组以存活。2)恶性疟原虫 线粒体使用以前未表征的基因表达系统进行抑制， 这种细胞器所特有的激活。目前的目标是确定 线粒体基因组之间的重组及其对耐药性的贡献，以及 以确定线粒体DNA修复途径和转录机制， 线粒体使用单细胞器的方法。该提案将确定和定义以前 寄生虫生物学的未知和未表征的方面，以推进合理的目标， 药物设计这些研究将完善我们对基因调控的基本机制的认识。 疟疾线粒体中的调节。研究这些影响的机制 将导致高度保守的药物开发靶点的鉴定。