Biophysical study of nanoscale structure and properties of lipid membrane and fundamental mechanisms of interactions of lipid membrane with antimicrobial and amyloid peptides

脂质膜纳米结构和性质的生物物理研究以及脂质膜与抗菌肽和淀粉样肽相互作用的基本机制

• 批准号: 298341-2012
• 负责人: Leonenko, Zoya
• 金额: $ 2.33万
• 依托单位: University of Waterloo
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=571481
• 关键词: Biophysical; study; nanoscale; structure; properties

Amyloid fibrils are insoluble protein aggregates which are associated with multiple neurodegenerative disorders, such as Alzheimer's disease. The molecular mechanism of amyloid toxicity is currently not well understood and requires a detailed understanding of the interactions of amyloid peptides with biomembrane. The biomembrane structure is complex and nonuniform as it is composed of small dynamic compartments called rafts. The detailed studies of the lipid rafts' nature and functions are important for the understanding of the molecular mechanisms of amyloid peptide binding to the membrane and their toxicity. I propose to investigate the similarities and differences between amyloid and antimicrobial peptides in order to understand the mechanism of their electrostatic interactions with lipid membranes. We will pay specific attention to the effect of lipid composition and cholesterol which induce raft formation and change electrostatic heterogeneity in the lipid membrane. We will combine atomic force microscopy (AFM) with the local surface potential measurements with the use of the most advanced modification of Kelvin probe force microscopy. In addition a combined AFM-patch clamp set up will be built to allow simultaneous AFM imaging and nanoscale electrical recording on a lipid membrane. These advanced scanning probe methods will allow us to investigate the nanoscale structure and physical properties of lipid membranes in order to understand how they may control membrane interactions with these peptides. The proposed research program will advance knowledge in the areas of membrane biophysics, as well as membrane-peptide interactions and will provide an insight into the role of lipid rafts in amyloidal and antimicrobial peptides action. This may promote the development of novel biomedical applications in relation to antimicrobial drug resistance or amyloid toxicity. In addition, the program will provide excellent interdisciplinary training for multiple students and researchers involved in this program.

淀粉样原纤维是不溶性蛋白质聚集体，与多种神经退行性疾病有关，例如阿尔茨海默病。淀粉样蛋白毒性的分子机制目前尚不清楚，需要详细了解淀粉样肽与生物膜的相互作用。生物膜结构复杂且不均匀，因为它由称为筏的小型动态隔室组成。对脂筏性质和功能的详细研究对于理解淀粉样肽与膜结合的分子机制及其毒性非常重要。我建议研究淀粉样蛋白和抗菌肽之间的异同，以了解它们与脂质膜静电相互作用的机制。我们将特别关注脂质成分和胆固醇的影响，它们诱导筏形成并改变脂质膜中的静电异质性。我们将使用最先进的开尔文探针力显微镜改进，将原子力显微镜 (AFM) 与局部表面电势测量结合起来。此外，还将建立一个组合的 AFM 膜片钳装置，以允许在脂质膜上同时进行 AFM 成像和纳米级电记录。这些先进的扫描探针方法将使我们能够研究脂质膜的纳米级结构和物理性质，以了解它们如何控制膜与这些肽的相互作用。拟议的研究计划将增进膜生物物理学以及膜-肽相互作用领域的知识，并将深入了解脂筏在淀粉样蛋白和抗菌肽作用中的作用。这可能会促进与抗菌药物耐药性或淀粉样蛋白毒性相关的新型生物医学应用的发展。此外，该项目将为参与该项目的多名学生和研究人员提供优秀的跨学科培训。