ROLE OF ATP-BINDING CASSETTE TRANSPORTERS IN INNATE INTESTINAL DEFENSE

ATP 结合盒转运蛋白在先天肠道防御中的作用

基本信息

  • 批准号:
    7304096
  • 负责人:
  • 金额:
    $ 21.9万
  • 依托单位:
  • 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:
    2007-08-01 至 2009-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The development of protective strategies against foodborne pathogens is critical for populations at risk. The food borne bacterium Listeria monocytogenes is responsible for considerable morbidity and mortality. The long-term goal of the proposed research is to elucidate innate defense mechanisms important for protection against enteric pathogens. Our global hypothesis is that the human ATP-dependent membrane transporter P-glycoprotein functions an innate defense mechanism against L. monocytogenes by modifying host cytoskeleton proteins required for invasion. We base this hypothesis on preliminary data demonstrating that 1) the extent of P-glycoprotein expression and function negatively correlate with the degree of L. monocytogenes invasion using in vivo and in vitro models, 2) P-glycoprotein transport activity is rapidly up-regulated during the invasion process and 3) the level of P-glycoprotein expression influences ¿-catenin cellular localization at baseline as well as mobilization during infection. Therefore, studies described in the current proposal are designed to investigate how P-glycoprotein protects the host against L. monocytogenes by focusing on host proteins required by the pathogen for invasion. SPECIFIC AIM 1: Determine if P-glycoprotein influences the localization, expression level or function of host proteins required for Listeria monocytogenes entry into cells. To accomplish this aim, we will employ the P-glycoprotein ON/OFF cell line and use confocal microscopy and Western immunoblotting to determine if the cellular localization or level of expression of cytoskeletal proteins is influenced by P-glycoprotein. We will also determine if P-glycoprotein alters signaling through two key host receptors. SPECIFIC AIM 2: Determine if P-glycoprotein influences the recruitment of host proteins during Listeria monocytogenes entry into cells. To accomplish this aim, we will employ the P-glycoprotein ON/OFF cell line and confocal microscopy to determine if the level of P-glycoprotein expression affects the normal recruitment or clustering of host proteins during invasion. In order to protect the public from foodborne pathogens, an understanding of innate defense mechanisms is required. Once this is accomplished, we can use this information to develop protective strategies that exploit these preexisting barriers to L. monocytogenes and potentially other pathogens.
描述(由申请方提供):制定针对食源性病原体的保护策略对风险人群至关重要。食源性细菌单核细胞增生李斯特菌是相当大的发病率和死亡率的原因。拟议研究的长期目标是阐明对肠道病原体保护重要的先天防御机制。我们的总体假设是,人类ATP依赖的膜转运蛋白P-糖蛋白的功能是一种先天防御机制,对L。单核细胞增多症通过修改宿主细胞骨架蛋白所需的入侵。我们的假设是基于以下初步数据:1)P-糖蛋白表达和功能的程度与L-糖蛋白的程度呈负相关。在使用体内和体外模型观察单核细胞增多症侵袭时,2)P-糖蛋白转运活性在侵袭过程中迅速上调,3)P-糖蛋白表达水平影响基线时的β-连环蛋白细胞定位以及感染期间的动员。因此,本研究旨在研究P-糖蛋白如何保护宿主免受L。通过关注病原体入侵所需的宿主蛋白质,来研究单核细胞增多症。具体目标1:确定P-糖蛋白是否影响单核细胞增生李斯特菌进入细胞所需的宿主蛋白的定位、表达水平或功能。为了实现这一目标,我们将采用P-糖蛋白ON/OFF细胞系,并使用共聚焦显微镜和Western免疫印迹法来确定细胞定位或细胞骨架蛋白的表达水平是否受到P-糖蛋白的影响。我们还将确定P-糖蛋白是否通过两个关键的宿主受体改变信号传导。具体目的2:确定P-糖蛋白是否影响单核细胞增生李斯特菌进入细胞过程中宿主蛋白的募集。为了实现这一目标,我们将采用P-糖蛋白ON/OFF细胞系和共聚焦显微镜,以确定P-糖蛋白的表达水平是否会影响正常的招聘或集群的主机蛋白在入侵。 为了保护公众免受食源性病原体的侵害,需要了解先天防御机制。一旦完成了这一点,我们就可以利用这些信息来制定保护策略,利用这些预先存在的障碍,以L。单核细胞增多症和潜在的其他病原体。

项目成果

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