CAREER: Liquid Crystallinity as a Tool to Probe Cell and Protein Behavior in Gel Biomaterials

职业：液晶性作为探测凝胶生物材料中细胞和蛋白质行为的工具

• 批准号: 1945057
• 负责人: Kelly Burke
• 金额: $ 58.25万
• 依托单位: University of Connecticut
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1945057&HistoricalAwards=false
• 关键词: CAREER; Liquid; Crystallinity; Tool; Probe

Mechanical properties of tissues can influence how individual cells behave. Changes in mechanical properties are often hallmarks of disease and are critical for healthy repair following injury. However, how the cells sense these properties at different length scales and how that information affects cell function are not well-understood. This CAREER research investigates new polymers that are compatible with human cells and can be used to surround cells for laboratory culture in three-dimensional (3D) gels. The polymers are liquid crystalline (LC), which means that they can be designed to order at different length scales. The research will establish new gel materials and determine how protein orders within the gels. The work will then determine how the length scales at which cells sense mechanical properties affect cell function, as well as investigate materials-based approaches to tune protein deposition/organization and cellular activation. The knowledge of cell behavior gained from this CAREER project can help discover and validate therapies for diseases such as fibrosis, a pathology characterized by excess scarring, and can contribute to new materials for regenerative medicine. The educational goal of this project is to provide fifth and sixth grade students, who are vulnerable along gendered lines to decreased self-efficacy in STEM, with opportunities to practice resilience or "grit", a measurable and trainable skill. Research-based activities will allow these students to attempt challenges and confront and overcome failure in a safe environment with support from undergraduate mentors. The integrated educational and research program aims to 1) teach resiliency skills to underserved students to increase attitudes of STEM self-efficacy, 2) train undergraduate and graduate students in research and to communicate research to diverse audiences, and 3) broadly distribute results of that research and generate interest in STEM. Part 2: Technical SummaryAnalysis of cell cultures in vitro generates knowledge of cell behavior and can reveal therapeutic targets, validate clinical therapies, and establish new materials for regenerative medicine. Mammalian cells alter function in response to culture substrates with different elastic and viscous (viscoelastic) properties, yet how cells sense viscoelasticity is not well understood. Given the heterogeneity of natural tissues, clarifying at what length scales (from microns to millimeters) cells sense and/or respond to viscoelasticity is hypothesized to be a critical design variable unaccounted for in current culture substrates. This project will establish a new class of cytocompatible, three-dimensional (3D) liquid crystalline (LC) gels, to enable encapsulation of cells in vitro and to pioneer new insight into cellular/subcellular responses to local 3D environments. The first objective will synthesize LC hydrogels and establish design parameters that control LC polymer order and material properties. The hydrogels will be combined with Type I collagen and fibroblasts to determine how LC polymer ordering affects the organization of reconstituted and de novo synthesized collagen. The second objective will quantify fibroblast activation and protein responses to changes in the viscoelasticity of the local 3D environment at varying length scales. The educational goal centers on resilience or "grit" as a measurable, trainable skill key to self-efficacy in STEM. A novel service learning model will integrate research with education, focusing on underrepresented students at the late elementary and early middle school level, a time when gender differences in STEM self-efficacy arise and affect both the rate at which students enter and continue with STEM studies. Research-integrated activities will allow 5th and 6th grade students to attempt challenges and confront and overcome failure in a safe environment with support from undergraduate student mentors. The integrated and sustainable educational and research program is expected to 1) teach resiliency skills to underserved students, 2) train undergraduate and graduate students in research and to communicate research to diverse audiences, and 3) broadly disseminate results and generate interest in STEM research.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

组织的机械特性可以影响单个细胞的行为。机械性能的变化通常是疾病的标志，对于损伤后的健康修复至关重要。然而，细胞如何在不同的长度尺度上感知这些特性，以及这些信息如何影响细胞功能，目前还没有很好的了解。这项CAREER研究调查了与人类细胞相容的新聚合物，可用于包围细胞，以便在三维（3D）凝胶中进行实验室培养。聚合物是液晶（LC），这意味着它们可以被设计为以不同的长度尺度排序。这项研究将建立新的凝胶材料，并确定蛋白质如何在凝胶中排列。然后，这项工作将确定细胞感知机械特性的长度尺度如何影响细胞功能，并研究基于材料的方法来调节蛋白质沉积/组织和细胞活化。从这个CAREER项目中获得的细胞行为知识可以帮助发现和验证纤维化等疾病的治疗方法，纤维化是一种以过度疤痕为特征的病理学，并可以为再生医学提供新材料。该项目的教育目标是为五年级和六年级学生提供机会，使他们有机会练习复原力或“毅力”，这是一种可衡量和可训练的技能，因为他们沿着性别线容易受到STEM自我效能降低的影响。以研究为基础的活动将允许这些学生尝试挑战，并在本科生导师的支持下，在安全的环境中面对和克服失败。综合教育和研究计划的目的是1）教弹性技能，以服务不足的学生，以提高STEM自我效能的态度，2）培训研究本科生和研究生，并向不同的受众传达研究，3）广泛分发研究结果，并产生对STEM的兴趣。第二部分：技术总结体外细胞培养物的分析产生细胞行为的知识，可以揭示治疗靶点，验证临床治疗，并建立再生医学的新材料。哺乳动物细胞改变功能，以响应不同的弹性和粘性（粘弹性）特性的培养基质，但细胞如何感觉粘弹性还没有很好地理解。鉴于天然组织的异质性，澄清在什么长度尺度（从微米到毫米）细胞的感觉和/或响应粘弹性假设是一个关键的设计变量未占在目前的培养基质。该项目将建立一类新的细胞相容性三维（3D）液晶（LC）凝胶，以实现体外细胞的封装，并开拓对局部3D环境的细胞/亚细胞反应的新见解。第一个目标是合成LC水凝胶，并建立控制LC聚合物顺序和材料性能的设计参数。水凝胶将与I型胶原和成纤维细胞结合，以确定LC聚合物排序如何影响重构和从头合成胶原的组织。第二个目标将量化成纤维细胞活化和蛋白质对不同长度尺度的局部3D环境粘弹性变化的反应。教育目标的中心是韧性或“勇气”，作为STEM自我效能的可衡量、可训练的技能。一种新的服务学习模式将研究与教育相结合，重点关注小学后期和初中早期代表性不足的学生，此时STEM自我效能感的性别差异出现，并影响学生进入和继续STEM学习的速度。研究综合活动将允许五年级和六年级的学生尝试挑战，面对和克服失败在一个安全的环境与本科生导师的支持。综合和可持续的教育和研究计划预计将1）教弹性技能，以服务不足的学生，2）培训本科生和研究生的研究，并沟通研究，以不同的观众，和3）广泛传播成果，激发对STEM研究的兴趣。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值进行评估，被认为值得支持和更广泛的影响审查标准。