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

职业：机械特性在淀粉样蛋白与细胞表面结合中的作用

• 批准号: 1054211
• 负责人: Justin Legleiter
• 金额: $ 40万
• 依托单位: West Virginia University Research Corporation
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1054211&HistoricalAwards=false
• 关键词: CAREER; Role; Mechanical; Properties; Amyloid

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

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它们对淀粉样肽及其聚集形式的敏感性。阿尔茨海默病（AB）的一个标志是AB的重排到非天然构象，促进有毒的纳米级聚集体的形成。阿尔茨海默病的最大危险因素是衰老，提出的工作旨在确定与衰老相关的细胞的机械变化如何增加AB结合细胞表面的能力。在这些研究中，暴露于AB之前，与年龄相关的膜变化将通过脂质双分子层的特定化学和组成变化来模拟，脂质双分子层是细胞膜的模型。同时，还将确定AB与培养细胞结合的能力，通过化学诱导的机械性能变化来模拟衰老。衰老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的破坏。扫描探针显微镜技术将应用于将模型脂质层和细胞的机械变化与它们对Ab结合和随后的破坏的易感性联系起来，以纳米尺度的空间分辨率测量。如果成功，该研究将详细了解与衰老相关的细胞表面特性如何影响AB膜的结合、聚集和最终毒性。Ab及其聚集体形式与细胞表面的结合代表了与AD相关的潜在毒性机制的基本步骤，并且在蛋白质/膜相互作用中具有更广泛的意义。该教育计划的重点是为职前科学、技术、工程和数学（STEM）教师提供有意义的研究经验，特别关注在阿巴拉契亚地区规划职业生涯的职前教师（pst），因为该地区经济困难县的人在STEM领域的代表性不足。pst将根据他们的研究活动开发可直接转化为课堂的课程或教学单元。据信，参与pst将能够改善该地区的科学教育

项目成果

Curvature Enhances Binding and Aggregation of Huntingtin at Lipid Membranes

• DOI: 10.1021/bi401619q
• 发表时间: 2014-04-15
• 期刊: BIOCHEMISTRY
• 影响因子: 2.9
• 作者: Chaibva, Maxmore;Burke, Kathleen A.;Legleiter, Justin
• 通讯作者: Legleiter, Justin

Mapping the Mechanical Properties of Cholesterol-Containing Supported Lipid Bilayers with Nanoscale Spatial Resolution

以纳米级空间分辨率绘制含胆固醇支撑脂质双层的机械性能

• DOI: 10.1021/la302705f
• 发表时间: 2012
• 期刊: Langmuir
• 影响因子: 3.9
• 作者: Shamitko-Klingensmith, Nicole;Molchanoff, Kelley M.;Burke, Kathleen A.;Magnone, George J.;Legleiter, Justin
• 通讯作者: Legleiter, Justin

The Interaction of Polyglutamine Peptides with Lipid Membranes Is Regulated by Flanking Sequences Associated with Huntingtin

• DOI: 10.1074/jbc.m112.446237
• 发表时间: 2013-05-24
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Burke, Kathleen A.;Kauffman, Karlina J.;Legleiter, Justin
• 通讯作者: Legleiter, Justin

Microtubule modification influences cellular response to amyloid-β exposure

微管修饰影响细胞对淀粉样蛋白-β 暴露的反应

• DOI: 10.3934/biophy.2016.2.261
• 发表时间: 2016
• 期刊: AIMS Biophysics
• 影响因子: 1.5
• 作者: Shamitko-Klingensmith, Nicole;W. Boyd, Jonathan;Legleiter, Justin
• 通讯作者: Legleiter, Justin

Investigation of temperature induced mechanical changes in supported bilayers by variants of tapping mode atomic force microscopy: Investigation of mechanical changes in bilayers

通过敲击模式原子力显微镜的变体研究温度引起的支撑双层的机械变化：研究双层的机械变化

• DOI: 10.1002/sca.21175
• 发表时间: 2015
• 期刊: Scanning
• 作者: Shamitko-Klingensmith, Nicole;Legleiter, Justin
• 通讯作者: Legleiter, Justin