Direct observation of the structure and function of cooperatively assembled membrane spanning pores formed by antimicrobial peptides.

项目描述：抗菌素耐药性的挑战激发了人们对了解先天免疫系统抗菌肽（AMP）机制的兴趣。AMP通常形成跨膜孔作为其杀菌活性的一部分，然而，组装和功能的精确机制仍然知之甚少。这部分是由于接口功能模型膜系统的技术，他们的interrogation.This项目的挑战将联合收割机多个单分子成像技术应用于模型膜[1]，研究已建立的和新的AMP肽相互作用的机制。通过单分子水平的研究，我们可以获得对跨膜孔组装机制的深入了解，通过这种方法，您将通过定量三色单分子成像来研究Magainin-II/PGLa的协同活性，以了解孔形成中肽-肽相互作用的性质[2]，并量化组装孔的活性动力学[3]。您还将这些技术扩展到团队开发的新型AMP [4]。了解这些孔的作用机制将提供对分子自组装的基本理解，同时确定孔本身的结构-功能关系，这是设计新型AMP的基础。测试的肽具有针对癌细胞的细胞毒性活性，因此这项研究可能为下一代治疗和药物递送系统创造机会。一旦在模型膜中实现了肽的表征，您将有机会在二维和三维细胞模型中研究它们的作用。研究环境：您将在物理-生命科学接口的多学科团队中工作，获得生物化学，单分子技术，膜合成生物学和细胞生物学等学科的经验。您将启动肽和蛋白质合成（Jin）和单分子膜成像（Castell）的旋转项目的研究，为研究项目提供基础。监督团队在监督和出版方面有着出色的记录，同时拥有独特的专业知识组合，您和项目将从中受益，例如人工膜和单分子方法（Castell），蛋白质/肽生物化学（Jin），AMP和细胞生物学（Jones）以及组织模型和生物成像（沃森）。我们的申请来自热情的科学家，他们在概述的一些领域（生物化学）具有适当的知识/经验/想法|蛋白质/肽处理|生物物理学|物理化学|具有跨学科学习的渴望，并在候选人的新领域发展。我们并不期望在所有领域都有经验。鼓励来自各种背景的有才华和热情的候选人申请。我们认识到，团队内部的多样性提供了更广泛的经验，观点和想法，可在解决问题和决策时借鉴。

Project Description:The challenge of antimicrobial resistance has ignited interest in understanding the mechanisms of antimicrobial peptides (AMPs) of the innate immune system. AMPs generally form membrane-spanning pores as part of their bactericidal activity, however, the precise mechanisms of assembly and function remain poorly understood. This is in part due to the challenges of interfacing functional model membrane systems with techniques for their interrogation.This project will combine multiple single molecule imaging techniques applied to model membranes [1] to study the mechanisms of peptide interaction of established and novel AMPs. By studying at the single molecule level we can gain otherwise inaccessible insight into the mechanisms of assembly of membrane spanning pores.With this approach you will study the synergistic activity of Magainin-II/PGLa by quantitative three-colour single-molecule imaging to understand the nature of peptide-peptide interactions [2] in pore formation, and quantify the activity dynamics of assembled pores [3]. You will also extend these techniques to novel AMPs developed by the team [4]. Understanding the mechanism of action of such pores will provide fundamental understanding into molecular self-assembly, alongside determining structure-function relationships of the pore itself, fundamental to design novel AMPs. The tested peptides possess cytotoxic activity against cancer cells, so this research may create opportunities for next generation therapeutics and drug delivery systems. Once peptide characterisation is achieved in model membranes you will have the opportunity to study their effect in 2-and-3D cell models.Research Environment: You will work within a multidisciplinary team at the physical-life science interface, gaining experience across disciplines from biochemistry, single molecule techniques, membrane synthetic biology and cell biology. You will initiate the research with rotational projects of peptide and protein synthesis (Jin), and single molecule membrane imaging (Castell), providing a foundation for the research project. The supervisory team have an excellent track record in supervision and publication, alongside a unique combination of expertise from which you and the project will benefit, - e.g. artificial membranes and single molecule methods (Castell), protein/peptide biochemistry (Jin), AMPs and cell biology (Jones) and tissue model and biological imaging (Watson). We applications from enthusiastic scientists with appropriate knowledge/experience/ideas in some of the areas outlined (biochemistry|protein/peptide handling|biological physics|physical chemistry|fluorescence) with an eagerness to learn across disciplines and develop in areas new to the candidate. We do not expect prior experience in all areas. Talented and enthusiastic candidates from all backgrounds are encouraged to apply. We recognise that diversity within a team provides a greater range of experience, perspectives and ideas to draw upon when tackling problems and informing decisions.