DETERMINANTS IN PLATELET MICROBICIDAL PROTEINS

血小板杀菌蛋白的决定因素

基本信息

批准号：
6751207
负责人：
Michael R Yeaman
金额：
$ 33.95万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-07-01 至 2007-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6751207
关键词：
antibiotics bactericidal immunity cellular immunity human subject laboratory rabbit microorganism immunology neutrophil phlebotomy platelets protein structure function

项目摘要

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.

描述（改编自申请人的摘要）：人类和兔子血小板含有血小板杀菌蛋白（PMP）。调查人员的数据表明，PMP在血小板抗菌功能中起关键作用。 PMP 针对抗生素耐药性血液施加有效的杀生性作用病原体，包括金黄色葡萄球菌和白色念珠菌。特定的PMP 从暴露于病原体或激动剂处的血小板中释放血管内感染，并在这些部位局部增强。 PMP敏感病原体在动物模型中的毒性要比其抗性PMP耐药性少。同行。这些令人信服的事实支持了他们的假设显着有助于抗菌宿主防御。 PMP最少对人血管内皮细胞或红细胞有毒，并明显不同在未释放的抗菌肽的结构和机制中进入血液。这些事实表明PMP具有关键功能决定因素这可以优化无伴随宿主细胞毒性的微生物活性。除了其杀菌作用之外，他们还发现PMP-2也增强中性粒细胞趋化性，吞噬作用和细胞内杀害。金黄色葡萄酒。 PMP-2具有与众不同的Cystine-X-Cystine（CXC）图案 α-α-变化代因，例如人血小板因子-4（HPF-4），它放大中性粒细胞的抗菌机制。这些事实表明PMP-2是施用直接杀生和施用的独特分子中性粒细胞抑制作用。研究者的中央假设争辩 PMP-2具有负责这些不同主机的特定决定因素国防功能。他们进一步假设可以定义这些决定因素，建模并用于建立关键的结构活性关系（SARS）管理特定功能。拟议的研究旨在探索这些假设。在PMP-2功能决定因素中定义SARS对他们最终的目标是设计具有强大和/或的反感染剂针对抗生素耐药病原体的选择性活性。因此，他们具体目的是：i）定义负责的结构决定因素 PMP-2的直接杀生功能； ii）定义PMP-2结构增强中性粒细胞抗菌功能的决定因素；和 iii）在PMP-2的抗菌决定因素中建立关键SAR。比较负责其有效和/或负责的PMP-2和HPF-4决定因素歧视性抗菌功能将使未来的人类PMP研究在人类无法进行的兔模型中。此外，SAR主题在PMP-2中发现将加速发现新型抗感染性抗病原体对常规药物的策略。因此，这些研究将大大提高我们对抗菌宿主的理解防御，并可能产生新模式以进行放大。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Efficacy of synthetic peptides RP-1 and AA-RP-1 against Leishmania species in vitro and in vivo.

合成肽 RP-1 和 AA-RP-1 对利什曼原虫的体外和体内功效。

DOI：
10.1128/aac.05349-11
发表时间：
2012
期刊：
Antimicrobial agents and chemotherapy
影响因子：
4.9
作者：
Erfe,MarieCriselB;David,ConsueloV;Huang,Cher;Lu,Victoria;Maretti-Mira,AnaClaudia;Haskell,Jacquelyn;Bruhn,KevinW;Yeaman,MichaelR;Craft,Noah
通讯作者：
Craft,Noah

Emerging themes and therapeutic prospects for anti-infective peptides.