MOLECULAR ANALYSIS OF MALARIA MITOCHONDRIAL GENE REGULATION

疟疾线粒体基因调控的分子分析

基本信息

批准号：
10543736
负责人：
Kristin D Lane
金额：
$ 41.39万
依托单位：
IDAHO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10543736
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 Life Cycle Stages 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 Translational Repression Translations drug development falls gene repression genome sequencing in vivo inhibitor member mitochondrial genome mutant new therapeutic target novel novel strategies novel therapeutic intervention novel therapeutics pressure protein complex reconstitution targeted treatment transcriptome whole genome

项目摘要

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.

人类疟原虫恶性疟原虫迅速产生耐药性，产生耐药性迫切需要新的治疗策略。识别和开发新产品的关键障碍药物开发目标是关于最重要流程和监管的知识差距途径。理想情况下，新靶点应该高度保守并且不能或能力有限变异以产生抗性。寄生虫线粒体功能至关重要跨越所有生命阶段，与人体细胞器有很大不同；然而，大多数疟原虫中的线粒体蛋白尚未被鉴定。红细胞内发育周期（IDC），恶性疟原虫由包含约约 20 个 6 kb 基因组拷贝，其特征是广泛重组。 IDC寄生虫线粒体不会使嵴插入电子传递链（ETC）酶，因此细胞器可能已经进化出独特的转录或翻译抑制系统来限制线粒体编码基因的表达。我们的综合方法结合的结果全基因组测序和代谢分析表明线粒体基因之间存在联系表达调节和对 ETC 抑制剂的抗性，可能是由于重组所致。因此，我们假设 1）多拷贝状态的一个特征是隐秘线粒体的保留编码突变等位基因的基因组拷贝，可以重组以求生存。 2) 恶性疟原虫线粒体使用以前未表征的基因表达系统来抑制和该细胞器特有的激活。目前的目标是确定来源线粒体基因组之间的重组及其对耐药性的贡献以及确定线粒体 DNA 修复途径和转录机制使用单细胞器方法的线粒体。该提案将确定并定义先前寄生虫生物学的未知和未表征的方面，其目标是推进理性药物设计。这些研究将完善我们对基因基本机制的认识疟疾线粒体的调节。研究这些影响的机制将导致高度保守的药物开发靶点的识别。