Host nutrient uptake and regulation by Toxoplasma

弓形虫对宿主营养的吸收和调节

• 批准号: 7425966
• 负责人: Isabelle Coppens
• 金额: $ 30.42万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7425966
• 关键词: 3-hydroxy-3-methylglutaryl-coenzyme A; Abbreviations; Acute; Address; Adverse effects; Affect; Anabolism; Binding Proteins; Biochemical Genetics; Biogenesis; Biological Process; Capsid Proteins; Cells; Cellular biology; Chinese Hamster Ovary Cell; Cholesterol; Cholesterol Esters; Cholesterol Homeostasis; Coenzyme A; Complex; Cytoplasm; DNA Sequence Rearrangement; Dihydrofolate Reductase; Drug Delivery Systems; EGF gene; Electron Microscopy; Endoplasmic Reticulum; Enzymes; Epidermal Growth Factor; Esters; Event; Exocytosis; Genomics; Glutathione S-Transferase; Goals; Human; Immunocompromised Host; Individual; Infection; Intercept; Life; Lipids; Lipoproteins; Low-Density Lipoproteins; Lysosomes; MAP Kinase Gene; Malaria; Mammalian Cell; Mediating; Medical; Membrane; Microtubule-Associated Proteins; Microtubules; Mitochondria; Mitogen-Activated Protein Kinases; Modification; Molecular; Nature; Neurologic; Nuclear Pore Complex; Nutrient; Nutritional; Organelles; Organism; Parasites; Pathway interactions; Pharmaceutical Preparations; Plasmodium; Process; Proteins; Purpose; Regulation; Regulatory Element; Research Personnel; Role; Source; Specificity; Staging; Sterol O-Acyltransferase; Sterols; System; Systemic disease; Therapeutic Intervention; Thymidylate Synthase; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Vacuole; base; citrate carrier; hypoxanthine-guanine-xanthine phosphoribosyltransferase; insight; interest; intracellular parasitism; novel; nutrition; obligate intracellular parasite; pathogen; rhoptry; sterol homeostasis; thymidylate synthase-dihydrofolate reductase; uptake

DESCRIPTION (provided by the applicant): Current treatments for the control of Toxoplasma gondii infections require long-term medication fraught with side effects and they are ineffective against the long-lived encysted stage, which is responsible for life threatening acute toxoplasmosis in immunocompromised individuals. The need for identifying novel drug targets is imperative. T. gondii is an obligate intracellular parasite, residing in a vacuole that is extensively modified by parasite secretions. It is speculated that the vacuolar parasite-induced modifications are largely for the purpose of nutrient uptake. However, essentially nothing is known about the nutritional needs of T. gondii. The strategies employed by Toxoplasma to access host nutrients and to regulate their supply will be characterized by using genomic, morphological, biochemical and genetic approaches. Host microtubules extend into the vacuolar space and induce the delivery of host lysosomes containing nutrients. The tubules mediating the lysosome delivery are then stabilized by the formation of a protein coat secreted by the parasite. A first aim of the proposal will focus on the molecular machinery underlying the reorganization of host microtubules around the Toxoplasma vacuole. The nature of the proteins forming the coat and their role in host lysosome scavenging into the vacuole will be studied. The primary source of T. gondii sterol is from lipoprotein uptake, a process that is specifically increased in infected cells. A second aim will address the alterations in cholesterol homeostasis in T. gondii-infected cells as well as the regulatory mechanisms developed by T. gondii to optimize cholesterol acquisition into proper organelles. The long-term goal of these studies is to reveal specificities in the pathways of nutrient acquisition which may offer opportunities for selective therapeutic intervention or to usurp these pathways for drug delivery. Simultaneously, this project is of broad cell biology interest and may provide insight into cholesterol homeostasis, microtubule dynamics and the mechanisms of membrane deformation in mammalian cells.

描述（由申请人提供）：目前控制弓形虫感染的治疗方法需要长期用药，且充满副作用，而且对长寿命包囊期无效，包囊期是免疫功能低下个体中危及生命的急性弓形虫病的原因。确定新药物靶点的需求势在必行。弓形虫是一种专性细胞内寄生虫，存在于被寄生虫分泌物广泛修饰的液泡中。据推测，液泡寄生虫诱导的修饰主要是为了营养吸收的目的。然而，对于弓形虫的营养需求基本上一无所知。弓形虫获取宿主营养物质并调节其供应的策略将通过使用基因组、形态学、生化和遗传方法来表征。宿主微管延伸到液泡空间并诱导含有营养物质的宿主溶酶体的输送。然后通过寄生虫分泌的蛋白质外壳的形成来稳定介导溶酶体递送的小管。该提案的第一个目标将集中于弓形虫液泡周围宿主微管重组的分子机制。将研究形成外壳的蛋白质的性质及其在宿主溶酶体清除进入液泡中的作用。弓形虫甾醇的主要来源是脂蛋白的摄取，这一过程在受感染的细胞中特别增加。第二个目标将解决弓形虫感染细胞中胆固醇稳态的变化，以及弓形虫开发的调节机制，以优化胆固醇获取到适当的细胞器中。这些研究的长期目标是揭示营养获取途径的特异性，这可能为选择性治疗干预或篡夺这些药物输送途径提供机会。同时，该项目具有广泛的细胞生物学意义，可以深入了解哺乳动物细胞中的胆固醇稳态、微管动力学和膜变形机制。