Staphylococcal Adaptations to Platelet Microbicidal Protein

葡萄球菌对血小板杀菌蛋白的适应

基本信息

批准号：
8022935
负责人：
ARNOLD S BAYER
金额：
$ 32.07万
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：
1996
资助国家：
美国
起止时间：
1996-12-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8022935
关键词：
Address Antimicrobial Cationic Peptides Antimicrobial Resistance Bacteria Biochemical Blood Platelets Catheters Cell Membrane Structures Cell membrane Characteristics Chemotactic Factors Clinical Clinical Treatment Communities Consensus Custom Cytoplasmic Granules Data Endocarditis Enzymes Etiology Event Exposure to Family Fatty Acids Figs - dietary Gene Expression Genes Genetic Grant Homeostasis Host Defense Human Immune system In Vitro Infection Invaded Investigation Laboratories Lesion Limb structure Link Lipids Liposomes Listeria Mediating Membrane Membrane Fluidity Membrane Lipids Mission Modeling Modification Molecular Profiling Nisin Organism Oryctolagus cuniculus Pathogenesis Pathway interactions Patients Peptide Antibiotics Peptides Phenotype Phospholipids Platelet Factor 4 Play Polymyxin B Predisposition Prevalence Proliferating Property Prosthesis Proteins Registries Relative (related person)Research Research Personnel Resistance Risk Factors Role Salmonella Sepsis Series Site Specificity Staphylococcus aureus Structure Syndrome System Techniques Thrombin Treatment Failure United States National Institutes of Health Vascular System Vesicle Work antimicrobial peptide base chemokine design in vivo induced pluripotent stem cell innovation killings knockout gene magainin microbicide novel palmitoylation pathogen platelet microbicidal protein prevent progenitor programs response translational approach

项目摘要

DESCRIPTION (provided by applicant): Antimicrobial peptides from platelets (termed platelet microbicidal proteins [PMPs]) play a critical role in the innate immune system especially in the context of host defenses against endovascular infections. During endovascular colonization, the invading organism must contend with this limb of the innate immune system to persist and proliferate at such sites of infection. The mechanisms by which the organism can circumvent the effects of PMPs to survive within the endovascular space are not well understood. This is especially true of "adaptive responses" that enable PMP-susceptible organisms to survive exposures to these peptides. This proposal will employ three integrated specific aims to address our overall hypothesis: the cell membranes of endovascular pathogens such as Staphylococcus aureus are able to respond to and survive PMP exposures by a coordinated series of lipid biosynthetic adaptations, termed "homeoviscous adaptations". The three specific aims will be: 1) to fully characterize the homeoviscous cell membrane responses in vitro; 2) to model these homeoviscous changes within customized liposomes ex vivo; and 3) to determine whether homeoviscous adaptations occur within relevant biomatrices and endovascular lesions in vivo. Aim 1 will utilize a series of in vitro techniques to examine the homeoviscous responses, including membrane fatty acid and phospholipid profiling, phospholipid assymetry and membrane fluidity. In addition, we will pair these analyses with a temporal assessment of expression by a series of prioritized membrane lipid biosynthetic genes. In Aim 2, we will employ large unilamellar vesicles whose membrane lipid contents will mirror those that emerge in vitro from Aim 1. These studies will define and quantify the impacts of homeoviscous adaptations on PMP:membrane interactions. Aim 3 will use the ex vivo biomatrix model and the rabbit model of endocarditis to explore the in vivo relevance of homeoviscous adaptations. The merging of in vitro-ex vivo-in vivo aspects of an important biologic event may well enable design of innovative strategies to prevent the organism from evolving these adaptations. This translational approach is within the mission of the NIH for their broad research roadmap. Lay Summary. The research in this proposal seeks to understand how bacteria can withstand the exposures to an important part of the host defense system (natural peptide antibiotics). This may enable design of new of strategies to kill such bacteria.

描述（由申请人提供）：来自血小板的抗菌肽（称为血小板杀微生物蛋白[PMP]）在先天免疫系统中发挥着关键作用，特别是在宿主防御血管内感染的情况下。在血管内定植期间，入侵的生物体必须与先天免疫系统的这一分支抗衡，才能在这些感染部位持续存在并增殖。生物体规避 PMP 影响而在血管内生存的机制尚不清楚。对于“适应性反应”尤其如此，这种反应使 PMP 易感生物体能够在暴露于这些肽的情况下存活下来。该提案将采用三个综合的具体目标来解决我们的总体假设：金黄色葡萄球菌等血管内病原体的细胞膜能够通过一系列协调一致的脂质生物合成适应（称为“同源粘性适应”）对 PMP 暴露做出反应并存活下来。这三个具体目标是：1）充分表征体外同卵粘性细胞膜反应； 2) 离体模拟定制脂质体中的这些同源粘性变化； 3) 确定体内相关生物基质和血管内病变内是否发生同体粘性适应。目标 1 将利用一系列体外技术来检查同卵粘性反应，包括膜脂肪酸和磷脂分析、磷脂不对称性和膜流动性。此外，我们将这些分析与一系列优先的膜脂生物合成基因的表达的时间评估结合起来。在目标 2 中，我们将采用大型单层囊泡，其膜脂含量将反映目标 1 体外出现的膜脂含量。这些研究将定义并量化同源粘性适应对 PMP：膜相互作用的影响。目标 3 将使用离体生物基质模型和兔心内膜炎模型来探索同卵粘性适应的体内相关性。重要生物事件的体外-离体-体内方面的融合很可能有助于设计创新策略，以防止生物体进化出这些适应能力。这种转化方法属于 NIH 广泛研究路线图的使命范围内。平铺总结。该提案中的研究旨在了解细菌如何能够承受宿主防御系统重要部分（天然肽抗生素）的暴露。这可能有助于设计新的策略来杀死此类细菌。