NRAMP1 AND PHAGOCYTE FUNCTION

NRAMP1 和吞噬细胞功能

• 批准号: 2672288
• 负责人: PHILIPPE GROS
• 金额: $ 16.79万
• 依托单位: MCGILL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-30 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2672288
• 关键词: Mycobacterium; cell type; disease /disorder proneness /risk; gene expression; gene mutation; genetically modified animals; granulocyte; host organism interaction; immunity; immunogenetics; laboratory mouse; macrophage; membrane proteins; microorganism immunology; nitric oxide; phagocytes; phagocytosis; protein transport; site directed mutagenesis; vesicle /vacuole

DESCRIPTION (Adapted from the applicant's abstract): Infectious diseases are a major health problem in North America, in part due to the widespread emergence of antibiotic-resistant pathogens. Tuberculosis (TB) is a dramatic example of this recurring threat, with the appearance of highly virulent and multidrug resistant M. tuberculosis(MTB), and the increased prevalence of TB in AIDS patients. The mechanisms of host defense against infection with intracellular parasites such as mycobacteria, and the bacterial strategies underlying long-term survival and replication in host phagocytes remain poorly understood. A better understanding of the host mechanisms of defense against such infections may suggest new strategies for intervention in these diseases. Using a genetic approach to study natural resistance and susceptibility traits in mouse models of human mycobacterial infections, the applicant has identified a new component of the antimicrobial defenses of phagocytes. In the mouse, replication of mycobacteria and other human intracellular pathogens including Salmonella, Leishmania, and Brucella, is controlled by the Bcg locus. The principal investigator cloned Bcg and showed that it encodes a phagocyte specific membrane protein (Nramp1) that shares structural characteristics of known ion transporters and channels. Nramp1 is recruited to the membrane of the phagosome soon after phagocytosis, and the principal investigator has proposed that the substrate of Nramp1 affects intraphagosomal microbial replication. The current proposal has four main goals. The first is to determine if the Nramp1 gene and protein are important for host defense against infection with MTB. For this, the effect of loss of Nramp1 in vivo on replication of MTB in reticuloendothelial organs and on overall mortality, will be evaluated. The second goal is to characterize the effect of Nramp1 association with the mycobacterial phagosome on the biochemical/physiological properties of this organelle, and on the survival of mycobacteria and Salmonella at that site. The third goal is to identify the mechanism of transport and the substrate of Nramp1. The fourth goal is to evaluate the extent of functional homology between the phagocyte-specific Nramp1 protein and the ubiquitously expressed Nramp2 protein. Together, these studies should clarify the mechanism of action of Nramp1 in the antimicrobial defenses of the phagocyte, which may in turn suggest new interventions against TB and other infectious diseases.

描述（改编自申请人摘要）：传染病 是北美的一个主要健康问题，部分原因是 抗药性病原体的出现。 结核病（TB）是一种 这种反复出现的威胁的一个戏剧性的例子， 毒力和多重耐药M.结核病（MTB）， 艾滋病患者结核病患病率。 宿主防御机制 感染细胞内寄生虫，如分枝杆菌， 细菌在宿主中长期存活和复制的策略 对吞噬细胞的了解仍然很少。 更好地了解主持人 对这种感染的防御机制可能会提出新的策略， 干预这些疾病。 用遗传学方法研究自然 人类分枝杆菌小鼠模型的耐药和敏感特性 感染，申请人已经确定了一个新的组成部分， 吞噬细胞的抗菌防御。 在小鼠中， 分枝杆菌和其它人类细胞内病原体包括沙门氏菌， 利什曼原虫和布鲁氏杆菌受Bcg基因座控制。 校长 研究人员克隆了Bcg，并表明它编码一种吞噬细胞特异性的 膜蛋白（Nramp1），具有已知的 离子转运体和通道。 Nramp1被募集到细胞膜， 吞噬后不久，吞噬体，和主要研究者有 提出Nramp1的底物影响吞噬体内的微生物， 复制的 目前的提案有四个主要目标。 一是 确定Nramp1基因和蛋白质对宿主防御是否重要 防止感染结核分枝杆菌。 为此，体内Nramp1缺失的影响 对网状内皮器官中MTB复制的影响以及对 死亡率，将进行评估。 第二个目标是描述 Nramp1与分枝杆菌吞噬体在 这种细胞器的生物化学/生理学特性，以及对生存的影响。 分枝杆菌和沙门氏菌的数量 第三个目标是确定 Nramp1的转运机制和底物。 第四个目标是 为了评估吞噬细胞特异性的 Nramp1蛋白和普遍表达的Nramp2蛋白。 在一起， 这些研究应该阐明Nramp1在 吞噬细胞的抗菌防御，这反过来可能表明新的 预防结核病和其他传染病的措施。