Novel nucleosome composition and modifications in protozoal parasite Toxoplasma g

原生动物寄生虫弓形虫 g 的新型核小体组成和修饰

基本信息

批准号：
8304864
负责人：
Sergio Oscar Angel
金额：
$ 10.98万
依托单位：
INSTITUTE/RESEARCH/BIOTECHNOLOGY FDN
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8304864
关键词：
ADP ribosylation Acetylation Acquired Immunodeficiency Syndrome Acute Acute Disease Address Apicomplexa Argentina Biology Bioterrorism C-terminal Categories Cellular Stress Centers for Disease Control and Prevention (U.S.)Chromatin Chromatin Remodeling Factor Chromatin Structure Chronic Chronic Disease Co-Immunoprecipitations Coin Collaborations Congenital Abnormality Cyst DNA DNA Folding Development Developmental Process Disease Docking Drug Delivery Systems Eimeria Enzymes Etiology Eukaryota Event Family Gene Expression Gene Expression Profile Gene Expression Regulation Genetic Genetic Transcription Genome Grant Health Histone Acetylation Histone Code Histone H2B Histone H4 Histones Homologous Gene Human Immunity Immunocompromised Host In Vitro Individual Infection Joints Knowledge Laboratories Lead Learning Life Life Cycle Stages Link Maps Methods Methylation Modification N-terminal Neurologic Nucleosomes Outcome Study Parasites Pathogenesis Pathogenicity Patients Phosphorylation Physiology Plasmodium Play Post-Translational Protein Processing Process Proteins Protozoa Publications Reading Reagent Role Site Staging Structure Surveys Tail Testing Tissues Toxoplasma Toxoplasma gondii Toxoplasmosis United States National Institutes of Health Variant Work Writing asexual base chromatin remodeling combinatorial dimer drug development histone modification in vivo insight mouse model novel pathogen promoter research study

项目摘要

DESCRIPTION (provided by applicant): The protozoan parasite Toxoplasma gondii is an important human and veterinary pathogen. In humans, acute disease is caused by rapidly growing 'tachyzoites' while chronic diseases is caused by latent 'bradyzoite' tissue cysts; both stages are essential for disease propagation and causation. Tachyzoites are responsible for congenital birth defects and latent bradyzoites represent a continual threat to immunocompromised (AIDS) patients. The interconversion process between tachyzoites and bradyzoites is central to the parasite's survival and pathogenicity, yet it remains poorly understood. Several lines of evidence have linked chromatin remodeling with parasite development into bradyzoite cysts, but the fundamental units of chromatin - histones - remain to be characterized in this important parasite. Our preliminary results show that T. gondii has a canonical H2A as well as two H2A variants (H2AX and H2AZ). In addition, it has a canonical H2B and H2B variant (H2Bv). The H2A and H2B class of histones and histone variants in T. gondii are unusual in sequence composition and how they interact. Thus a major gap in our knowledge is how T. gondii nucleosomes are structured and post-translationally modified in the different stages of the parasite. In specific aim 1 we will determine the configuration of H2A and H2B histones in T. gondii nucleosomes and will analyze nucleosome composition of active and silent chromatin during bradyzoite development. In specific aim 2 we will identify non-histone proteins associating with T. gondii H2As and H2Bs histones during in both tachyzoites and bradyzoites. Determination of the non-histone proteins that associate with these histone variants is essential to learn more about the function of these histones in parasite physiology, and will illuminate the key proteins regulating the reading and writing of the Toxoplasma histone code. In specific aim 3, we will construct a post-translational modification map of T. gondii H2As and H2Bs histones in the different parasite stages. Given the sequence disparity and unusual variants in the T. gondii histone classes, it is important to identify the post-translational modifications on these histones during tachyzoite and bradyzoite stages. PUBLIC HEALTH RELEVANCE Toxoplasma gondii has achieved notoriety as a cause of life-threatening opportunistic disease in immunocompromised individuals. In addition, with the growing threat of bioterrorism this parasite is now listed as a Category B pathogen in the NIH/CDC list of priority pathogens. The proposal will produce a significant impact in elucidating the genetic basis and mechanisms underlying development in Toxoplasma parasites with a great potential of identifying novel drug targets against toxoplasmic chronic infection

描述（由申请人提供）：原生动物寄生虫弓形虫Gondii是重要的人类和兽医病原体。在人类中，急性疾病是由迅速生长的“次杀虫”引起的，而慢性疾病是由潜在的“ Bradyzoite”组织囊肿引起的。这两个阶段对于疾病的传播和因果关系至关重要。 tachyzoites负责先天性先天缺陷，而潜在的胸肌则代表了对免疫功能低下（AIDS）患者的持续威胁。速氮和Bradyzoites之间的相互转换过程是寄生虫的生存和致病性的核心，但仍然鲜为人知。几种证据将染色质的重塑与寄生虫的发育联系起来与牛皮岩囊肿联系起来，但是在这种重要的寄生虫中，染色质的基本单位仍然有待表征。我们的初步结果表明，T。gondii具有一个规范的H2A以及两个H2A变体（H2AX和H2AZ）。此外，它具有规范的H2B和H2B变体（H2BV）。 T. gondii中的组蛋白和组蛋白变体的H2A和H2B类别在序列组成上是不寻常的及其相互作用的。因此，我们所知的一个主要差距是如何在寄生虫的不同阶段进行结构和翻译后修饰。在特定的目标1中，我们将确定gondii核小体中H2a和H2b组蛋白的构型，并将分析在Bradyzoite发育过程中活性和沉默染色质的核小体组成。在特定的目标2中，我们将在tachyzoites和bradyzoites中鉴定与T. gondii H2AS和H2BS组蛋白相关联的非历史蛋白。确定与这些组蛋白变体相关的非固定蛋白对于更多地了解这些组蛋白在寄生虫生理学中的功能至关重要，并将阐明调节毒素组蛋白代码的读取和写作的关键蛋白质。在特定的目标3中，我们将在不同的寄生虫阶段构建gondii H2A和H2BS组蛋白的翻译后修饰图。鉴于T. gondii组蛋白类别中的序列差异和异常变体，重要的是在tachyzoite和bradyzoite阶段识别这些组蛋白的翻译后修饰很重要。公共卫生相关性的毒质量贡迪（Gondii）成为了免疫功能低下的个体威胁生命的机会性疾病的臭名昭著的。此外，随着生物恐怖的威胁日益增长，该寄生虫现在被列为NIH/CDC优先病原体清单中的B类病原体。该提案将在阐明弓形虫寄生虫发展的遗传基础和机制方面产生重大影响

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Epichromatin is conserved in Toxoplasma gondii and labels the exterior parasite chromatin throughout the cell cycle.

DOI：
10.1017/s0031182013000504
发表时间：
2013-08
期刊：
Parasitology
影响因子：
2.4
作者：
Vanagas L;Dalmasso MC;Dubremetz JF;Portiansky EL;Olins DE;Angel SO
通讯作者：
Angel SO

Protein palmitoylation in protozoan parasites.

原生动物寄生虫中的蛋白质棕榈酰化。

DOI：
10.2741/211
发表时间：
2011
期刊：
Frontiers in bioscience (Scholar edition)
影响因子：
0
作者：
Corvi,MariaMartha;Berthiaume,LucGerard;DeNapoli,MaximilianoGabriel
通讯作者：
DeNapoli,MaximilianoGabriel

A review of recent patents on the protozoan parasite HSP90 as a drug target.

DOI：
10.2174/1872208311307010002
发表时间：
2013-04-01
期刊：
Recent patents on biotechnology
影响因子：
0
作者：
Angel, Sergio O;Matrajt, Mariana;Echeverria, Pablo C
通讯作者：
Echeverria, Pablo C

N-terminal palmitoylation is required for Toxoplasma gondii HSP20 inner membrane complex localization.

DOI：
10.1016/j.bbamcr.2013.02.022
发表时间：
2013-06
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
影响因子：
5.1
作者：
De Napoli, M. G.;de Miguel, N.;Lebrun, M.;Moreno, S. N. J.;Angel, S. O.;Corvi, M. M.
通讯作者：
Corvi, M. M.

Protein palmitoylation and pathogenesis in apicomplexan parasites.