EAGER: A detailed investigation of topic modeling of CBET research

这个EAGER项目是“高风险高回报”，因为它涉及一种全新的方法来研究肽-脂质界面相互作用的机制，使用一种称为耗散石英晶体微天平（QCM-D）的自由振荡传感器。生命取决于生物膜的完整性及其维持功能的能力。智力优势。利用多肽破坏细菌细胞膜完整性是杀灭有毒细菌的一种新策略。或者，保护哺乳动物细胞膜免受肽或寡聚体的破坏是减轻阿尔茨海默病的一种策略。s（和许多其他淀粉样蛋白相关）疾病（AD）。在这两种情况下，很少有人知道肽如何结合到生物膜（或膜模拟物称为支持的脂质双层，SLB），以及它们如何聚集和渗透形成孔和/或诱导脂质损失。各种相互作用模型包括形成吸附在SLB表面上的肽，在有和没有从SLB释放脂质的情况下形成孔。以前，诸如界面张力（LB）、泄漏、光谱学（NMR、EPR、CD）和散射测量（用光、X射线和中子的反射测量）的方法已被用于分析蛋白质-脂质相互作用。局限性包括存在非天然的脂质-空气界面（LB）和低灵敏度（NMR，EPR）。使用荧光或电流变化的泄漏测量对于确定SBL的邻接性是有用的，但不能提供太多的机械见解。散射技术是对所提出的QCM-D测量的补充，并将在橡树岭国家实验室（我们在2012年秋季进行中子反射测量的建议是成功的）对这里描述的相同问题进行研究。这是一个复杂的界面结合，破坏和运输的挑战，发生在SLB的表面。本研究提出了一种新的技术QCM-D，用于研究不同肽和SBL之间的界面和转运问题，以期设计出更有效的肽，并为抑制Aâ破坏奠定基础。本研究计划测量两种不同家族的两亲肽之间的界面相互作用和转运（抗菌素、抗菌肽、淀粉样蛋白A A A A）和模型膜（SLB），以发现更有效的抗菌肽，为预防A A A破坏奠定基础，其实验方案、材料选择和测量技术相结合都是新颖的。没有人已经制定了一个广泛接受的机制肽诱导的破坏模型细胞膜，如SLB的规则。我们的新方法将测量两个独立的参数，频率和耗散的变化，或质量和刚度的变化，分别和结合动力学。他们最近取得了进展，并首次观察到AMP（picidin 1 - 3）和A纤维对SLB的破坏。在低浓度下，picidin 1 - 3似乎形成孔状结构，而在高浓度下，它们提取部分双层，并在SLB中形成胶束和大空腔。拟议研究的结果很重要，因为它们将有助于建立更有效地破坏细菌膜完整性的设计原则，并制定保护哺乳动物细胞膜免受肽或寡聚体破坏的策略。这两个具体目标是：目标一：通过AMPS研究细菌样SLBs的破裂机制，目的II：通过Aâ 1 -42寡聚物研究细菌样SLMs的崩解机制。拟议的研究将提供一个基本的了解肽与SLB的相互作用。这与灭活细菌感染和减轻淀粉样蛋白疾病（如阿尔茨海默病）有广泛的相关性。s，亨廷顿？s，帕金森？s和其他20多个。随着细菌对抗生素的耐药性增加，迫切需要新的和不同的方法来处理细菌感染。用AMP灭活细菌提供了一种令人兴奋的抗生素替代品。这项研究的结果将有利于社会优化AMP设计的治疗和涂层医院的墙壁，以灭活空气传播的细菌。该项目将促进培训和学习，通过伦斯勒大学本科研究计划让本科科学和工程专业的学生参与，并通过RPI Questar计划让高中高年级学生参与。将再次招募女性和少数民族学生，以扩大代表性不足的群体的参与，让学生接触现代界面科学。

This EAGER project is "high risk high payoff" in that it involves a radically new approach to investigate the mechanism of peptide-lipid interfacial interactions using a freely oscillating sensor called a Quartz Crystal Microbalance with Dissipation (QCM-D). Life depends on the integrity of biological membranes and their ability to maintain function. Intellectual Merit. Disrupting bacterial membrane integrity with peptides on purpose is a new strategy to kill toxic bacteria. Alternately, protecting mammalian cell membrane from disruption by peptides or oligomers is a strategy to mitigate Alzheimer?s (and many other amyloid-related) disease(s) (AD). In both cases, very little is known about how the peptides bind to biological membranes (or to membrane mimics called supported lipid bilayers, SLBs) and how they aggregate and penetrate to form pores and/or induce lipid loss. Various models of interaction include the formation peptide adsorbed on a SLB surface, pore formation with and without release of lipids from a SLB. Previously, methods such as interfacial tension (Langmuir-Blodgett (LB)), leakage, spectroscopy (NMR, EPR, CD) and scattering measurements (reflectometry with light, X-rays and neutrons) have been used to analyze protein-lipid interactions. Limitations include the presence of a nonnatural lipid-air interface (LB) and low sensitivity (NMR, EPR). Leakage measurements using fluorescence or electrical current changes are useful for determining the contiguity of the SBLs but do not provide much mechanistic insight. Scattering techniques are complementary to the proposed QCM-D measurements and will be pursued at Oak Ridge National Labs (our proposal to conduct neutron reflectometry in the Fall 2012 was successful) on the same problem described here. This is a complex interfacial binding, disruption and transport challenge, which occurs at the surface of SLBs. The PIs propose the use of a novel technique, QCM-D, to interrogate this interfacial and transport problem with a variety of peptides and SBLs with the hope of designing more potent peptides and establishing a foundation for inhibiting Aâ disruption.The PIs plan to measure the interfacial interactions and transport between two different families of amphipathic peptides (anti-microbial, AMPs, and amyloid protein, Aâ) and model membranes (SLBs) in order to discover more potent AMPs and establish a basis to prevent Aâ disruption.Their experimental plan of attack, materials choice and technique of measurement in combination are novel. No one has developed rules for a widely accepted mechanism of peptideinduced disruption of model cell membranes like SLBs. Our new approach will measure two independent parameters, changes in frequency and dissipation, or changes in mass and rigidity, respectively, and binding kinetics. They have recently made progress and observed disruption of SLBs with both AMPs (picidin 1 & 3) and Aâ fibrils for the first time. At low concentrations, picidin 1 & 3 appear to form porelike structures while at high concentrations, they extract parts of the bilayer and form micelles and large cavities in the SLB. The results from the proposed study are important because they will help establish design principles with greater efficacy to disrupt bacterial membrane integrity and formulate strategies to protect mammalian cell membranes from disruption by peptides or oligomers. The two specific goals are: Aim I: Investigate the rupture mechanism of bacterial-like SLBs by AMPS, and Aim II: Investigate the disintegration mechanism of mammalian-like SLMs by Aâ1-42 oligomer species.Broader Impact. The proposed study will provide a fundamental understanding of the interactions of peptides with SLBs. This has broad relevance to inactivating bacterial infections and to mitigating amyloid diseases like Alzheimer?s, Huntington?s, Parkinson?s and over 20 others. As bacteria increase resistance to antibiotics, new and different methods are urgently needed to deal with bacterial infection. Deactivating bacteria with AMPs offers an exciting alterative to antibiotics. Results of this research will benefit society by optimizing AMP design for treatment and for coating hospital walls to deactivate airborn bacteria. The project will promote training and learning by involving undergraduate science and engineering majors through the Rensselaer Undergraduate Research Program and by involving high school seniors through the RPI Questar program. Female and minority students will again be recruited to broaden participation of underrepresented groups, exposing students to modern interfacial science.