Malaria HATs in Transcription Regulation

转录调控中的疟疾 HAT

基本信息

批准号：
7334210
负责人：
LIWANG CUI
金额：
$ 36.5万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7334210
关键词：
Acetyl Coenzyme A Affinity Chromatography Antigenic Switching Antimalarials Antineoplastic Agents Antiparasitic Agents Area Binding Biochemical Biological Biological Assay Biology Cell physiology Chromatin Chromatin Remodeling Factor Chromatin Structure Co-Immunoprecipitations Complex Country Coupled DNA Microarray Chip DNA Microarray format DNA Packaging Development Disease Disruption Drug Delivery Systems Drug resistance Enzymes Epigenetic Process Eukaryota Eukaryotic Cell Family Family member Gene Expression Gene Expression Regulation Gene Targeting Genetic Genetic Transcription Genome Growth and Development function Histone Acetylation Histone Deacetylase Histone H2A Histones Immunoblot Analysis In Vitro Knock-out Lead Lysine Malaria Mass Spectrum Analysis Mediating Microarray Analysis Modification Molecular Mutation N-terminal Nucleosomes Parasite Control Parasites Pharmaceutical Preparations Plasmodium Plasmodium falciparum Play Post-Translational Protein Processing Prevalence Proteins Public Health Research Research Personnel Role Role playing therapy Screening procedure Substrate Specificity Tail Transcriptional Regulation Transfection Virulence Yeasts base chemotherapy chromatin immunoprecipitation design histone acetyltransferase in vivo interest novel preference programs promoter yeast two hybrid system

项目摘要

The increasing burden of malaria, in part, due to drug resistance in the parasite Plasmodium falciparum, demands new therapies. Recent research in the field of transcription has demonstrated the functional importance of chromatin in regulating gene expression in eukaryotes. Enzymes that modulate chromatin structures have a profound effect on controlling gene expression. Among these enzymes, histone acetyltransferases (HATs), which transfer the acetyl group from acetyl-CoA to the lysine residues in the N- terminal tails of histones, are the best studied. The antiparasitic effects of drugs that disturb histone acetylation and recent studies from our group on the chromatin remodeling factors in P.falciparum demonstrated that dynamic histone acetylation is an important epigenetic mechanism of transcription regulation and plays a prominent role in development of the malaria parasite. Thus, we propose to 1) characterize two families of transcription-related HAT proteins, 2) determine their functional roles in global transcription regulation, and 3) identify the subunits of multiprotein HAT complexes in P. falciparum. HAT proteins will be characterized using molecular and biochemical approaches, and their functions in parasite development and transcription regulation will be determined by targeted gene disruption and genome-wide expression analysis. This proposed research aims to reveal the epigenetic mechanisms in transcription regulation that controls the parasite development and virulence. The fundamental importance of histone acetylation in gene regulation and the great potential of HAT and histone deacetylase as drug targets underline the significance of research in this area, which may lead to novel antimalarial drugs. Malaria is still a major public health problem in many countries. Its recent resurgence in prevalence is partially due to drug resistance. This study aims to characterize the functions of a group of enzymes that regulate parasite gene expression, which may lead to the design of novel antimalarial drugs.

疟疾负担的增加部分是由于恶性疟原虫的耐药性，需要新的疗法。转录领域的最新研究证明了该功能染色质在调节真核生物中基因表达中的重要性。调节染色质的酶结构对控制基因表达具有深远的作用。在这些酶中，组蛋白乙酰基转移酶（HATS），将乙酰基从乙酰辅酶A转移到N-的N-中的赖氨酸残基组蛋白的终端尾巴是最好的研究。干扰组蛋白的药物的抗寄生虫作用乙酰化和我们小组的最新研究对粉状质量重塑因子证明动态组蛋白乙酰化是转录的重要表观遗传机理监管和在疟原虫的发展中起着重要作用。因此，我们建议1）表征两个与转录相关的帽子蛋白的家族，2）确定它们在全球中的功能作用转录调节，3）识别恶性疟原虫中多蛋白帽复合物的亚基。帽子蛋白质将使用分子和生化方法进行表征，它们的功能在寄生虫中的功能开发和转录调控将由靶向基因破坏和全基因组确定表达分析。这项拟议的研究旨在揭示转录的表观遗传机制控制寄生虫发育和毒力的调节。组蛋白的基本重要性基因调节中的乙酰化以及HAT和组蛋白脱乙酰基酶的巨大潜力作为药物靶标强调了该领域研究的重要性，这可能导致新型抗疟药。在许多国家，疟疾仍然是一个主要的公共卫生问题。它最近在患病率上的复兴是部分原因是耐药性。这项研究旨在表征一组酶的功能调节寄生虫基因表达，这可能导致新型抗疟药的设计。