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：
7371138
负责人：
ARNOLD S BAYER
金额：
$ 33.37万
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 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7371138
关键词：
Address Antimicrobial Cationic Peptides Antimicrobial Resistance Appendix 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 Invasive 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 Role playing therapy 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 concept design in vivo 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（称为血小板杀菌蛋白[PMPS]）的抗菌肽在先天免疫系统中起着至关重要的作用，尤其是在宿主防御抗血管内感染的情况下。在血管内定植期间，入侵的生物必须与先天免疫系统的这个肢体抗衡，才能在这种感染部位持续和增殖。生物体可以规避PMP在血管内空间内生存的作用的机制尚不清楚。对于“适应性反应”，使PMP敏感的生物能够生存在这些肽中的暴露中，这尤其如此。该提案将采用三个集成的特定目的来解决我们的整体假设：血管内病原体的细胞膜（例如金黄色葡萄球菌）能够通过一系列脂质生物合成的适应来应对和生存PMP暴露，称为“主场适应”。这三个特定的目标将是：1）在体外充分表征本垒打的细胞膜反应； 2）模拟自定义脂质体内的这些本垒打变化； 3）确定在体内相关的生物疗法和血管内病变中是否发生了本土适应。 AIM 1将利用一系列体外技术来检查本土反应，包括膜脂肪酸和磷脂谱，磷脂囊泡和膜流动性。此外，我们将将这些分析与表达的时间评估与一系列优先的膜脂质生物合成基因相结合。在AIM 2中，我们将采用大型的单层囊泡，其膜脂质含量将反映出AIM 1体外的囊泡。这些研究将定义和量化本土适应对PMP的影响：膜相互作用。 AIM 3将使用体内生物机模型和心内膜炎的兔模型来探索本土适应的体内相关性。重要生物学事件的体外体内体内各个方面的合并可以很好地设计创新策略，以防止生物体不断发展这些适应性。这种翻译方法是NIH的任务，用于其广泛的研究路线图。摘要摘要。该提案中的研究旨在了解细菌如何承受对宿主防御系统（天然肽抗生素）的重要部分的暴露。这可能使设计新的策略杀死这种细菌。