Malaria HATs in Transcription Regulation

转录调控中的疟疾 HAT

基本信息

批准号：
7195291
负责人：
LIWANG CUI
金额：
$ 31.93万
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/7195291
关键词：
Acetyl Coenzyme A Affinity Chromatography Antigenic Switching Antimalarials Antineoplastic 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

DESCRIPTION (provided by applicant): 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 anti-parasitic 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.

描述（由申请人提供）：疟疾的负担增加，部分原因是寄生虫恶性疟原虫的耐药性需要新的疗法。转录领域的最新研究表明，染色质在调节真核生物中基因表达方面的功能重要性。调节染色质结构的酶对控制基因表达具有深远的作用。在这些酶中，最好的研究是最好的研究，这些酶是组蛋白N-末端尾巴中的乙酰基-COA转移到乙酰辅酶A到赖氨酸残基的组蛋白乙酰基转移酶（HATS）。扰动组蛋白乙酰化的药物的抗寄生作用以及我们小组对恶性疟原虫染色质重塑因子的最新研究表明，动态组蛋白乙酰化是转录调节的重要表观遗传机制，并且在疟原虫寄生虫的发育中起着重要的作用。因此，我们建议1）表征两个与转录相关的HAT蛋白家族，2）确定它们在全球转录调控中的功能作用，3）确定恶性疟原虫中多蛋白质HAT复合物的亚基。 HAT蛋白将使用分子和生化方法来表征，它们在寄生虫发育和转录调控中的功能将由靶向基因破坏和全基因组表达分析确定。这项拟议的研究旨在揭示控制寄生虫发育和毒力的转录调节中的表观遗传机制。组蛋白乙酰化在基因调节中的基本重要性以及HAT和组蛋白脱乙酰基酶作为药物靶标的巨大潜力强调了该领域的研究的重要性，这可能导致新型的抗疟药。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部分是由于耐药性。这项研究旨在表征调节寄生虫基因表达的一组酶的功能，这可能导致新型抗疟药的设计。