NRAMP1 AND PHAGOCYTE FUNCTION

描述（改编自申请人的摘要）：传染病 是北美的一个主要健康问题，部分原因是广泛传播 抗生素耐药病原体的出现。 结核病 (TB) 是一种 这种反复出现的威胁的戏剧性例子， 有毒力和多重耐药性结核分枝杆菌（MTB），以及增加 艾滋病患者中结核病的患病率。 宿主防御机制 细胞内寄生虫（例如分枝杆菌）感染，以及 宿主长期生存和复制的细菌策略 吞噬细胞仍然知之甚少。 对楼主有更好的了解 防御此类感染的机制可能会提出新的策略 对这些疾病进行干预。 使用遗传学方法研究自然 人类分枝杆菌小鼠模型的耐药性和易感性特征 感染，申请人已经确定了该药物的新成分 吞噬细胞的抗菌防御。 在小鼠中，复制 分枝杆菌和其他人类细胞内病原体，包括沙门氏菌， 利什曼原虫和布鲁氏菌均由 Bcg 基因座控制。 校长 研究人员克隆了 Bcg，并表明它编码吞噬细胞特异性 膜蛋白 (Nramp1) 具有已知结构特征 离子转运体和通道。 Nramp1 被招募到细胞膜上 吞噬作用后不久就被吞噬体吞噬，主要研究者已经 提出 Nramp1 的底物影响吞噬体内微生物 复制。 当前的提案有四个主要目标。 第一个是 确定 Nramp1 基因和蛋白质对于宿主防御是否重要 预防 MTB 感染。 为此，体内 Nramp1 缺失的影响 MTB 在网状内皮器官中的复制和整体 死亡率，将进行评估。 第二个目标是表征效果 Nramp1 与分枝杆菌吞噬体的关联 该细胞器的生化/生理特性及其对生存的影响 该部位的分枝杆菌和沙门氏菌。 第三个目标是确定 Nramp1 的运输机制和底物。 第四个目标是 评估吞噬细胞特异性之间的功能同源性程度 Nramp1 蛋白和普遍表达的 Nramp2 蛋白。 在一起， 这些研究应该阐明 Nramp1 的作用机制 吞噬细胞的抗菌防御，这可能反过来表明新的 针对结核病和其他传染病的干预措施。

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.