Saccharide-Based Effectors of Cationic Antimicrobial Peptides

阳离子抗菌肽的糖基效应物

• 批准号: 7267903
• 负责人: Robert John Kerns
• 金额: $ 17.9万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7267903
• 关键词: Saccharide; Based; Effectors; Cationic; Antimicrobial

DESCRIPTION (provided by applicant): The long-term objective of initiating this research program is to characterize the effect of endogenous glycosaminoglycans (GAGs) and exogenous sulfated saccharides on the function of cationic antimicrobial peptides (CAPs) in innate immunity against pathogens. In order to understand the effects of GAGs and sulfated saccharides on CAPs it is vital to first identify the individual GAGs and sulfated saccharides that bind CAPs and inhibit CAP antibacterial activity, and to characterize these interactions. The specific goal of this exploratory R21 study is to break new ground in understanding the structural requirements for endogenous GAGs and exogenous sulfated saccharides to bind CAPs and inhibit CAP antibacterial activity. In Aim 1 we will systematically identify the endogenous GAGs that bind to and inhibit antibacterial activity of individual CAPs and classes of CAPs. Susceptibility testing will be employed to quantify inhibition of CAP antibacterial activity by GAGs and GAG derivatives. Binding studies will be employed to ascertain correlations between GAG-CAP affinity and GAG inhibition of CAP activity. Completion of Aim 1 will enable future studies to dissect the role of specific CAP-GAG interactions in the infective and virulence processes of microorganisms. In Aim 2 we will determine the effect of sulfated saccharides that are in clinical use or clinical development on the antibacterial activity of individual CAPs. The central question we will answer is - Which specific types of sulfated saccharides inhibit antibacterial activity of specific CAPs in vitro, and thus have the potential to inhibit innate immune response in vivo? Completion of Aim 2 will enable future studies to determine the in vivo effects of sulfated saccharides on CAP function. Experiments in Aim 3 focus on characterizing the concentration-dependent inhibition of CAP antibacterial activity by GAGs versus GAGs protecting CAPs from proteolytic degradation. These experiments will test the hypothesis that GAGs protect CAPs from proteolytic degradation at concentrations insufficient to block CAP antibacterial activity. Relevance to public health: Molecules called antimicrobial peptides defend the body against microorganisms such as viruses and bacteria. In this study we are working to determine how activity of these antimicrobial peptides is affected by another class of molecules in the body, the glycosaminoglycans. We are also investigating if certain types of therapeutic agents inhibit antibacterial activity of the antimicrobial peptides.

描述（由申请人提供）：启动本研究计划的长期目标是表征内源性糖胺聚糖（GAG）和外源硫酸化糖对阳离子抗菌肽（CAP）在针对病原体的先天免疫中的功能的影响。为了了解 GAG 和硫酸化糖对 CAP 的影响，至关重要的是首先识别结合 CAP 并抑制 CAP 抗菌活性的单个 GAG 和硫酸化糖，并表征这些相互作用。这项探索性 R21 研究的具体目标是在理解内源性 GAG 和外源性硫酸化糖结合 CAP 并抑制 CAP 抗菌活性的结构要求方面开辟新的领域。在目标 1 中，我们将系统地识别与单个 CAP 和各类 CAP 结合并抑制其抗菌活性的内源性 GAG。将采用药敏试验来量化 GAG 和 GAG 衍生物对 CAP 抗菌活性的抑制作用。将采用结合研究来确定 GAG-CAP 亲和力和 GAG 对 CAP 活性的抑制之间的相关性。目标 1 的完成将使未来的研究能够剖析特定 CAP-GAG 相互作用在微生物感染和毒力过程中的作用。在目标 2 中，我们将确定临床使用或临床开发中的硫酸糖对单个 CAP 抗菌活性的影响。我们要回答的核心问题是 - 哪些特定类型的硫酸化糖在体外抑制特定 CAP 的抗菌活性，从而有可能在体内抑制先天免疫反应？目标 2 的完成将使未来的研究能够确定硫酸化糖对 CAP 功能的体内影响。目标 3 中的实验侧重于表征 GAG 对 CAP 抗菌活性的浓度依赖性抑制作用与保护 CAP 免受蛋白水解降解的 GAG 的作用。这些实验将检验以下假设：GAG 在浓度不足以阻止 CAP 抗菌活性的情况下保护 CAP 免受蛋白水解降解。与公共卫生的相关性：称为抗菌肽的分子可以保护身体免受病毒和细菌等微生物的侵害。在这项研究中，我们正在努力确定这些抗菌肽的活性如何受到体内另一类分子（糖胺聚糖）的影响。我们还在研究某些类型的治疗剂是否会抑制抗菌肽的抗菌活性。