Dissecting the roles of protein O-GlcNAcylation in Toxoplasma gondii

剖析蛋白 O-GlcNAc 酰化在弓形虫中的作用

• 批准号: 8719923
• 负责人: Kami Kim
• 金额: $ 20.88万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-12 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8719923
• 关键词: Acetylglucosamine; Acquired Immunodeficiency Syndrome; Affect; Apicomplexa; Biochemical; Biological Process; Chemistry; Congenital Abnormality; Development; Disease; Enzymes; Epigenetic Process; Eukaryota; Gene Expression Regulation; Genes; Genetic Transcription; Glycoproteins; Human; Immune; Individual; Infection Control; Investigation; Life; Life Cycle Stages; Mediating; Mediator of activation protein; Metabolism; Nutrient; O-GlcNAc transferase; Organism; Parasites; Pathogenesis; Patients; Pregnancy; Process; Proteins; Role; Serine; Signal Transduction; Signaling Molecule; Site; Spontaneous abortion; Staging; Stress; System; Testing; Threonine; Toxoplasma gondii; Transcriptional Regulation; Validation; Woman; abortion; base; comparative; genetic regulatory protein; glycosylation; interest; obligate intracellular parasite; pathogen; prevent; protein transport; public health relevance; response

DESCRIPTION (provided by applicant): Toxoplasma gondii is an obligate intracellular parasite in the phylum Apicomplexa. This parasite causes life-threatening diseases in AIDS patients and immune-compromised individuals, and birth defects or abortions when women are infected during pregnancy. An essential process for pathogenesis and persistence of T. gondii in human hosts is the interconversion between the rapidly dividing tachyzoites and latent bradyzoites. Despite its pathological significance, the signaling molecules and the mechanisms underlying this process are poorly understood. Recently, ubiquitous O-GlcNAcylation and O-GlcNAc transferase (OGT), the enzyme that catalyzes this process, have been identified in T. gondii. OGT adds a single ¿-N-acetylglucosamine to serine or threonine residues of intracellular proteins. Because in mammalian organisms, O-GlcNAc is a mediator of intracellular signaling, transcription regulation, and protein trafficking in response to cellular nutrients or stress, we hypothesize that O-GlcNAc may serve as an active player in T. gondii's life cycle transition between tachyzoites and bradyzoites by dynamically modifying intracellular proteins. To test this hypothesis, we will use a chemoenzymatic approach to identify O-GlcNAc-modified proteins in T. gondii tachyzoites (Aim 1). Next, we will apply this approach for comparative analysis of changes in protein O-GlcNAc status in T. gondii tachyzoite-bradyzoites transition. We will focus our studies on gene-regulatory proteins that are involved in this process. Once identified, we will characterize the role of O-GlcNAc in mediating the biological functions of these modified proteins in this life-cycle transition (Aim 2). Finally, we will characterize how changes in global protein O-GlcNAcylation mediated by OGT influence the life-cycle transition of T. gondii (Aim 3).

描述（由适用提供）：弓形虫Gondii是门神经膜中的强制性细胞内寄生虫。这种寄生虫在艾滋病患者和免疫受损的个体中引起威胁生命的疾病，以及在怀孕期间妇女感染时出生缺陷或堕胎。人类宿主中T. gondii的发病机理和持久性的一个基本过程是迅速分裂的速氮和潜在的Bradyzoites之间的相互转化。尽管具有病理意义，但该过程的信号传导分子和机制知之甚少。最近，在T. gondii中已经鉴定出了无处不在的O-Glcnacylation和O-GlCNAC转移酶（OGT），即催化这一过程的酶。 OGT在细胞内蛋白的系列或苏氨酸残留物中添加了单个€-N-乙酰葡萄糖。因为在哺乳动物的生物中，O-GLCNAC是对细胞内信号传导，转录调节和蛋白质运输的介体，响应细胞营养或压力，我们假设O-GlCNAC可以通过tachyzoites和Bradyzoite Intractifeins Intracellical Inteceins Intracellical Intipeceins在T. Gondii的生命周期转移中成为活跃的参与者。为了检验这一假设，我们将使用一种化学酶方法来鉴定巨型t. gondii速二氏菌中的O-GlCNAC修饰蛋白（AIM 1）。接下来，我们将采用这种方法进行比较分析gondii tachyzoite-bradyzoite the蛋白O-GLCNAC状态的变化。我们将把研究重点放在与此过程有关的基因调节蛋白上。一旦确定，我们将 表征O-GlCNAC在介导这些修饰蛋白在生命周期过渡中的生物学功能中的作用（AIM 2）。最后，我们将表征全局的变化 OGT介导的蛋白O-Glcnacylation会影响T. gondii的生命周期过渡（AIM 3）。