Host nutrient uptake and regulation by Toxoplasma

弓形虫对宿主营养的吸收和调节

• 批准号: 6807975
• 负责人: Isabelle Coppens
• 金额: $ 34.5万
• 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 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6807975
• 关键词: SDS polyacrylamide gel electrophoresis; Toxoplasma gondii; cholesterol; host organism interaction; immunoelectron microscopy; intracellular parasitism; lysosomes; microtubule associated protein; microtubules; nutrient intake activity; nutrition related tag; polymerase chain reaction; toxoplasmosis; two dimensional gel electrophoresis; vesicle /vacuole

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）：当前控制弓形虫感染的治疗方法需要长期用副作用的药物，它们对长期寿命的百科全阶段无效，这对不受影响的个体中的急性造成生命的急性毒质量造成了威胁。必须确定新型药物靶标的需求。 T. gondii是一种义务的细胞内寄生虫，位于液泡中，该液泡通过寄生虫分泌进行了广泛修饰。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。但是，从本质上讲，对于T. gondii的营养需求一无所知。弓形虫采用的获取宿主营养并调节其供应的策略将以基因组，形态学，生化和遗传方法来表征。宿主微管延伸到液泡空间中，并诱导含有养分的宿主溶酶体的递送。然后，通过由寄生虫分泌的蛋白质涂层形成介导溶酶体递送的小管稳定。该提案的第一个目的将集中于托克斯玛液泡周围宿主微管重组的基础的分子机制。将研究形成外套的蛋白质的性质及其在宿主溶酶体中的作用，将研究液泡清除液泡。 T. gondii固醇的主要来源来自脂蛋白的摄取，该过程在感染细胞中特异性增加。第二个目的将解决gondii感染细胞中胆固醇稳态的改变，以及T. gondii开发的调节机制，以将胆固醇的获取优化为适当的细胞器。这些研究的长期目标是揭示养分获取途径的特异性，这可能为选择性治疗干预提供机会，或篡夺这些途径以输送药物。同时，该项目具有广泛的细胞生物学兴趣，并可能提供有关胆固醇稳态，微管动力学以及哺乳动物细胞中膜变形的机制的见解。