DETERMINANTS IN PLATELET MICROBICIDAL PROTEINS

描述（改编自申请人摘要）：人和兔 血小板含有血小板杀微生物蛋白（PMP）。调查人员的 数据显示PMPs在血小板抗微生物功能中起关键作用。PMPs 对耐药性血流发挥有效的杀菌作用 病原体，包括金黄色葡萄球菌和白色念珠菌。具体的PMP 从暴露于病原体或激动剂的血小板中释放， 血管内感染，并在这些部位局部加重。PMP敏感 病原体在动物模型中的毒性低于其同基因PMP抗性 同行这些令人信服的事实支持他们的假设， 显著有助于抗微生物宿主防御。PMP最低限度 对人血管内皮细胞或红细胞有毒性， 在结构和机制上， 进入血液。这些事实表明，PMP具有关键的功能决定因素 其优化了杀微生物活性而没有伴随宿主细胞毒性。 除了杀菌作用，他们还发现PMP-2还 增强嗜中性粒细胞的趋化性、吞噬作用和胞内杀伤S. 金黄色。PMP-2具有胱氨酸-X-胱氨酸（CXC）基序， α-趋化因子如人血小板因子-4（HPF-4）， 中性粒细胞的抗菌机制。这些事实表明，PMP-2是一种 独特的分子，发挥直接杀微生物和 嗜中性粒细胞增强作用。研究人员的核心假设认为， PMP-2具有特定决定因素， 防御功能。他们进一步假设这些决定因素可以被定义， 建模，并用于建立关键结构-活性关系（SAR） 管理具体职能。拟议的研究旨在探索 这些假设。在PMP-2功能决定因子中定义SAR对于 他们的最终目标是设计具有强效和/或 对耐药性病原体的选择性活性。因此双方的 具体目标是：（一）确定结构决定因素， PMP-2的直接杀微生物功能; ii）定义PMP-2的结构 增强嗜中性粒细胞抗菌功能的决定因素;以及 iii）建立PMP-2抗菌决定簇的关键SAR。比较 PMP-2和HPF-4决定因素，负责其有效和/或 区别性的抗菌功能将使未来的研究人类PMPs 在兔子模型中进行，而这在人类中是无法进行的。此外，SAR主题 在PMP-2中发现的新基因将加速新型抗感染药物的发现 针对对常规药剂具有抗药性的病原体的战略。因此这些 这些研究将极大地促进我们对抗菌宿主的理解， 防御，并可能产生新的模式，其放大。

DESCRIPTION (Adapted from the Applicant's Abstract): Human and rabbit platelets contain platelet microbicidal proteins (PMPs). The investigators' data show that PMPs play key roles in platelet antimicrobial functions. PMPs exert potent microbicidal actions against antibiotic-resistant bloodstream pathogens, including Staphylococcus aureus and Candida albicans. Specific PMPs are released from platelets exposed to pathogens or agonists at sites of endovascular infection, and intensify locally at these sites. PMP-susceptible pathogens are less virulent in animal models than their isogenic PMP-resistant counterparts. These compelling facts support their hypothesis that PMPs significantly contribute to antimicrobial host defense. PMPs are minimally toxic to human vascular endothelial cells or erythrocytes, and differ markedly in structure and mechanism from antimicrobial peptides that are not released into the bloodstream. These facts suggest PMPs have key functional determinants that optimize microbicidal activity without concomitant host cytotoxicity. Beyond its microbicidal effects, they have discovered that PMP-2 also potentiates neutrophil chemotaxis, phagocytosis and intracellular killing of S. aureus. PMP-2 has a cystine-X-cystine (CXC) motif distinctive of alpha-chemokines such as human platelet factor-4 (hPF-4) that amplify antimicrobial mechanisms of neutrophils. These facts indicate that PMP-2 is a unique molecule that exerts both direct microbicidal and neutrophil-potentiating effects. The investigators' central hypothesis contends that PMP-2 has specific determinants responsible for these distinct host defense functions. They further hypothesize these determinants can be defined, modeled, and used to establish key structure-activity relationships (SARs) governing specific functions. The proposed studies are designed to explore these hypotheses. Defining SARs in PMP-2 functional determinants is crucial to their eventual goal of designing anti-infective agents with potent and/or selective activity against antibiotic-resistant pathogens. Therefore, their Specific Aims are: i) to define the structural determinants responsible for direct microbicidal functions of PMP-2; ii) define the PMP-2 structural determinants that potentiate the antimicrobial functions of neutrophils; and iii) establish the key SARs in antimicrobial determinants of PMP-2. Comparison of PMP-2 and hPF-4 determinants responsible for their potent and/or discriminative antimicrobial functions will enable future studies of human PMPs in the rabbit model that cannot be conducted in humans. Moreover, SAR themes discovered in PMP-2 will accelerate discovery of novel anti-infective strategies against pathogens resistant to conventional agents. Thus, these studies will significantly advance our understanding of antimicrobial host defense, and may yield new modes for its amplification.