NRAMPL AND PHAGOCYTE FUNCTION

描述（改编自申请人的摘要）：传染病具有 在北美重新成为一个主要的健康问题，部分原因是 抗生素耐药性的普遍出现。 结核病是一个戏剧性的 这种威胁的一个例子是， 抗性M.结核病，以及艾滋病患者中结核病的流行。 的 防御细胞内寄生虫的机制，以及细菌 宿主吞噬细胞中生存和复制的基本策略仍然很差 明白 更好地了解宿主对此类感染的防御 可能为这些疾病的干预提出新的策略。 使用遗传 方法，PI已经确定了一种新的抗微生物成分（Nramp1） 吞噬细胞的防御 小鼠中Nramp1的突变导致对 几种细胞内感染和人NRAMP1的多态性变体， 与结核病和麻风病易感性有关。 Nramp1是一个膜转运蛋白大家族的一部分， Nramp1在溶酶体中表达， 巨噬细胞的隔室，并靶向细菌的膜 吞噬后不久吞噬体。 通过与已知底物的同源性， 其他Nramp家族成员，建议Nramp1作为二价 吞噬体膜上的阳离子外排泵，以抑制细菌 复制的 目前的提案有五个主要目标。 一是研究 在小鼠中，Nramp1和其他基因在调节结核分枝杆菌复制中的作用 在肺部。 第二个是了解Nramp1交付如何影响 吞噬体的生理特性，包括成熟、酸化 和杀菌活性。 Nramp1在中性粒细胞功能中的作用也将 被研究。 第三个目标是确定的底物和机制， Nramp 1在吞噬体膜上的转运。 四是识别 负责Nramp1靶向溶酶体的蛋白决定簇， 对底物结合和运输至关重要的残基。 五是学习 在正常人的二价阳离子转运中，近端Nramp2同源物的作用 组织，包括吞噬体膜。 总之，这些研究应该 阐明Nramp1在吞噬细胞抗微生物中的作用及作用机制 这反过来可能为结核病的干预提供新的途径， 其他传染病。

DESCRIPTION (Adapted from the Applicant's Abstract): Infectious diseases have re-emerged as a major health problem in North America, in part die to the widespread emergence of antibiotic resistance. Tuberculosis is a dramatic example of this threat, with the appearance of highly virulent and multidrug resistant M. tuberculosis, and the prevalence of TB in AIDS patients. The mechanisms of defense against intracellular parasites, and the bacterial strategies underlying survival and replication in host phagocytes remain poorly understood. A better understanding of host defenses against such infections may suggest new strategies for intervention in these diseases. Using a genetic approach, the PI has identified a new component (Nramp1) of anti-microbial defenses of phagocytes. Mutations at Nramp1 in mice cause susceptibility to several intracellular infections, and polymorphic variants at human NRAMP1 are associated with susceptibility to TB and leprosy in endemic areas of disease. Nramp1 is part of a large family of membrane transporters that has been highly conserved from bacteria to man. Nramp1 is expressed in the lysosomal compartment of macrophages and is targeted to the membrane of bacterial phagosomes soon after phagocytosis. By homology with the known substrates of other Nramp family members, it is proposed that Nramp1 functions as a divalent cation efflux pump at the phagosomal membrane to suppress bacterial replication. The current proposal has five major goals. The first is to study in the mouse the role of Nramp1 and other genes in regulating Mtb replication in the lungs. The second is to understand how Nramp1 delivery affects the physiological properties of the phagosome including maturation, acidification and bactericidal activity. The role of Nramp1 in neutrophil function will also be studied. The third goal is to identify the substrate and mechanism of transport of Nramp1 at the phagosomal membrane. The fourth is to identify protein determinants responsible for Nramp1 targeting to the lysosome and residues essential for substrate binding and transport. The fifth is to study the role of the close Nramp2 homologue in divalent cation transport in normal tissues, including at the phagosomal membrane. Together, these studies should clarify the role and mechanism of action of Nramp1 in phagocyte anti-microbial defenses, which may in turn suggest new avenues for intervention in TB and other infectious diseases.