BRIGE: In Vitro Cellular Model of Amyloid Plaque Formation Using Combinatorial Libraries of Micro-nano-hybrid Topographies with Tunable Elasticity

BRIGE：使用弹性可调的微纳米混合拓扑结构组合文库的淀粉样斑块形成的体外细胞模型

• 批准号: 1227766
• 负责人: Yong Yang
• 金额: $ 17.5万
• 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: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1227766&HistoricalAwards=false
• 关键词: BRIGE; Vitro; Cellular; Model; Amyloid

PI: Yang, YongProposal Number: 1227766The objective of this project is to develop combinatorial libraries of highly defined micro-nanohybrid topographies with tunable elasticity to build an in vitro model of amyloid plaque formation from neural cells for understanding and alleviating Alzheimer's disease (AD). The overall goal is to delineate the molecular mechanism by which transgenic neural cells generate amyloid plaques in a biomimetic microenvironment and discover pharmaceutical targets against AD. Intellectual Merit: Amyloid plaque formation is a neuropathological hallmark of Alzheimer's disease (AD) which is the most prominent cause of dementia in the elderly. It is caused by the extracellular deposition of aggregated amyloid-beta (A-beta) peptides in the brain. In vivo studies reveal that the amyloid plaque's formation changes the local microenvironment, subsequently leading to neuronal alterations, eventually neurodegeneration. Inhibition of amyloid plaque formation represents a feasible therapeutic target against AD. The current lack of in vitro models of amyloid plaques formed from neural cells greatly limits the progress in seeking strategies to inhibit amyloid plaque formationand identifying therapeutic targets. There is, therefore, a critical need for the development of cell culture technologies in a biomimetic manner that can be reproducibly applied to regulate neural cell behavior to facilitate formation of amyloid plaques for AD research and therapeutic development. Because neural cells as well as A-beta aggregation are highly sensitive to surface properties of the substrate, it is hypothesized that the amyloid plaque formation can be recapitulated by culturing neural cells on highly defined micro-nano-hybrid topographies with tunable elasticity. To test this hypothesis, the PI following specific tasks are proposed: 1) Produce highly defined micro-nano-hybrid topography; 2) Precisely tune the level of elasticity of hydrogels at nanoscale; 3) Engineer combinatorial libraries of micro-nano-hybrid topographies with tunable elasticity to build an in vitro cellular model of amyloid plaque formation.At the completion of this project, the PI expects to have developed the technologies necessary to produce well-defined micro-nano-hybrid topography and to fine tune substrate elasticity at the nanoscale. With these enabling technologies, combinatorial libraries of micro-/nano hybrid topographies with tunable elasticity is engineered to facilitate the establishment of in vitro cellular model of amyloid plaque formation, which is not only crucial to the elucidation of the fundamental of amyloid plaque formation, but will also contribute to understand and alleviate AD. Broader Impacts: As an indispensable part of this proposal, extensive Education and Outreach activities have been planned to broaden the participation of individuals from underrepresented groups. Graduate and undergraduate students, especially women and minority students will be involved into every aspect of the multidisciplinary research. Graduate students will work on bothEngineering and Health Science campuses at WVU, will be taught polymer nanoscience and nanoengineering, and appreciate cell culture and characterization skills at the molecular and cellular levels. Undergraduate students will obtain hands-on research experience to deepen their understanding of scientific principles and to relate classroom knowledge to phenomena they observe in the real world. Moreover, projects comprising teaching modules and lab demonstrations will be developed and integrated into existing outreach events at WVU, especially the weeklong Engineers of Tomorrow summer camp designed to encourage Appalachian area G9-12 students, in particular young women and minorities, to participate in a science or engineering field. Nanobiotechnology will be publicized on Nano Days in Children's Discovery Museum of West Virginia to excite the children and increase public awareness of nanobiotechnology. This project will further collaborative research with health science researchers and foster collaborations with local industries.

PI：Yang，Yongproposal编号：1227766该项目的目的是开发具有可调弹性的高度定义的微纳米杂交构图的组合库，以建立从神经细胞形成的体外模型，以理解和减轻阿尔茨海默氏病（AD）（AD）。总体目标是描述转基因神经细胞在仿生微环境中产生淀粉样蛋白斑块的分子机制，并发现针对AD的药物靶标。智力优点：淀粉样菌斑形成是阿尔茨海默氏病（AD）的神经病理学标志，这是老年痴呆症最突出的原因。它是由大脑中聚集的淀粉样蛋白β（A-BETA）肽的细胞外沉积引起的。体内研究表明，淀粉样菌斑的形成改变了局部微环境，随后导致神经元改变，最终导致神经变性。抑制淀粉样斑块的形成代表了针对AD的可行治疗靶标。目前，由神经细胞形成的淀粉样斑块的体外模型缺乏体外模型极大地限制了寻求抑制淀粉样淀粉菌斑形成和识别治疗靶标的策略的进步。因此，以生物映射的方式需要开发细胞培养技术，可以重复应用来调节神经细胞行为，以促进淀粉样蛋白斑块的形成，以进行AD研究和治疗性发育。 由于神经细胞以及A-beta聚集对底物的表面特性高度敏感，因此可以假设可以通过在高度定义的微纳米杂种型杂交板上培养神经细胞，并具有可调节性的弹性来概括淀粉样蛋白斑块的形成。为了检验这一假设，提出了以下特定任务的PI：1）产生高度定义的微纳米杂种地形； 2）精确调整纳米级水凝胶弹性水平； 3) Engineer combinatorial libraries of micro-nano-hybrid topographies with tunable elasticity to build an in vitro cellular model of amyloid plaque formation.At the completion of this project, the PI expects to have developed the technologies necessary to produce well-defined micro-nano-hybrid topography and to fine tune substrate elasticity at the nanoscale.借助这些能力技术，具有可调弹性的微型/纳米混合形形的组合库可以促进建立淀粉样淀粉样板块形成的体外细胞模型，这不仅对阐明淀粉样植物的基本形式的基本形式至关重要，而且还将撰写和撰写。更广泛的影响：作为该提案不可或缺的一部分，已计划开展广泛的教育和外展活动，以扩大人数不足的团体的个人参与。研究生和本科生，尤其是妇女和少数族裔学生将参与多学科研究的各个方面。研究生将在WVU的Bothewermering和健康科学校园工作，将教授聚合物纳米科学和纳米工程，并在分子和细胞水平上欣赏细胞培养和表征能力。本科生将获得动手研究经验，以加深他们对科学原则的理解，并将课堂知识与他们在现实世界中观察到的现象联系起来。此外，将开发包括教学模块和实验室演示的项目，并将其融入WVU的现有外展活动，尤其是明天夏令营的为期一周的工程师，旨在鼓励阿巴拉契亚地区G9-12学生，尤其是年轻妇女和少数族裔，以参加科学或工程领域。 Nanobiotechnology将在西弗吉尼亚州儿童发现博物馆的纳米时代公布，以激发儿童并提高公众对纳米生物技术的认识。该项目将与健康科学研究人员进行进一步的合作研究，并促进与当地行业的合作。