CAREER: The Role of Mechanical Properties in Amyloid Binding to Cellular Surfaces

该奖项的研究目标是了解细胞中与年龄相关的机械变化如何增加其对淀粉样肽及其聚集形式结合的敏感性。阿尔茨海默病（AB）的标志是Ab重排为非天然构象，其促进有毒的纳米级聚集体的形成。AD最大的危险因素是衰老，这项工作的目的是确定与衰老相关的细胞机械变化如何增加AB结合细胞表面的能力。在这些研究中，与年龄相关的膜改变将通过特定的脂双层化学和成分改变来模拟，脂双层是细胞质膜的模型，在暴露于AB之前。与此同时，还将测定AB与培养细胞结合的能力，以及化学诱导的机械性能变化，以模拟老化。与此相关的变化包括氧化损伤、膜胆固醇含量增加和细胞骨架成分破坏。扫描探针显微镜技术将被应用于关联的机械变化，测量与纳米空间分辨率，模型lipidbilayer和细胞与他们的易感性抗体结合和随后的disruption.If成功，拟议的研究将产生详细的了解细胞表面特性与老化如何影响AB膜的结合，聚集，和ultimatelytoxicity。抗体及其聚集体与细胞表面的结合是AD潜在毒性机制的基础，并在蛋白质/膜相互作用中具有更广泛的意义。该教育计划的重点是提供有意义的研究经验，职前科学，技术，工程和数学（STEM）教师，特别关注职前教师（PST）在阿巴拉契亚地区的职业规划，因为来自经济贫困县的人在该地区的STEM领域代表性不足。PST将根据他们的研究活动开发一个课程或可教单元，可以直接转化为课堂。相信参与的PST将能够改善该地区的科学教育

The research objective of this award is to gain an understanding of how age-related mechanicalchanges in cells increase their susceptibility to being bound by the amyloid peptide andits aggregate forms. A hallmark of Alzheimer's disease (AB) is the rearrangement of the Ab to anon-native conformation that promotes the formation of toxic, nanoscale aggregates. Thelargest risk factor for AD is aging, and the proposed work aims to determine how mechanicalchanges in cells associated with aging increases the ability of AB to bind cellular surfaces. Forthese studies, age-related alterations of membranes will be mimicked by specific chemical andcompositional alterations to lipid bilayers, which are models of a cells plasma membrane, priorto exposure to AB. In parallel, the ability of AB to bind to cells in culture, with chemically inducedchanges in mechanical properties designed to mimic ageing, will also be determined. Agerelatedchanges include oxidative damage, enhanced cholesterol content of the membrane, anddisruption of cytoskeletal components. Scanning probe microscopy techniques will be applied tocorrelate mechanical changes, measured with nanoscale spatial resolution, of the model lipidbilayers and cells with their susceptibility to Ab binding and subsequent disruption.If successful, the proposed research would yield detailed understanding of how cellular surfaceproperties associated with aging influence AB membrane binding, aggregation, and ultimatelytoxicity. The binding of Ab and its aggregate forms to cellular surfaces represents a fundamentalstep in potential toxic mechanisms associated with AD and has broader implications inprotein/membrane interactions. The educational plan focuses on providing meaningful researchexperience to pre-service science, technology, engineering, and mathematics (STEM) teachers,with a particular focus on pre-service teachers (PSTs) planning on careers in the region ofAppalachia, as persons from economically-distressed counties in this region areunderrepresented in STEM fields. The PSTs will develop a lesson or teachable unit based ontheir research activities that can be directly translated into the classroom. It is believed thatparticipating PSTs will be able to improving science education in the region