Single-molecule studies of hyaluronic acid

透明质酸的单分子研究

• 批准号: 1611497
• 负责人: Omar Saleh
• 金额: $ 39万
• 依托单位: University of California-Santa Barbara
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1611497&HistoricalAwards=false
• 关键词: Single; molecule; studies; hyaluronic; acid

Non-technical: This award by the Biomaterials program in the Division of Materials Research to University of California-Santa Barbara is to study the size, shape and solution properties of hyaluronic acid (hyaluronan, HA) in the presence of salts and other molecules that binds with this polymer. Hyaluronan, or hyaluronic acid (HA), is a huge polymer molecule that defines the structure and mechanics of many spaces in the human body such as tissue hydration, wound healing, lubrication of certain biological interfaces, and helps to define the mechanics of joints and functionality. Further, HA is under active investigation for use in biomaterials applications, notably functionalized HA gels that act as cell/tissue engineering substrates. These functions of HA rely on its polymeric, random-walk structure, which is modulated by solution conditions, including salt concentration, crowding by other biological polymers, and the presence of HA-binding molecules. It is thus of basic importance, for both biological and chemical reasons, to have a detailed understanding of the microscopic basis of HA conformation and solution behavior. The proposed studies are expected to lead to a better understanding of HA's various biological roles, as well as to permit rational engineering of HA-based biomaterials. Further, carrying out this project would have a variety of important broader impacts, including strengthening university/national lab partnerships, and training young scientists, at both undergraduate and graduate levels in an interdisciplinary scientific area with excellent long-term potential. International dissemination and scientific exchanges are parts of this project, and these unique activities are important in achieving scientific broader impacts. Technical: Hyaluronic acid (HA) is a polysaccharide present in nearly all mammalian tissues. HA is characterized by a large anionic charge density, conformational flexibility, and polymorphism due to a variety of hydrogen-bonding interactions. These features, along with its association with certain ligands, lead it to define the mechanical and viscoelastic properties of extracellular spaces, such as the pericellular matrix, eye vitreous, and synovial fluid. HA is of further interest for clinical applications, and as a biomaterial used to create gel substrates for cell and tissue growth. In all these biological and biomaterials applications, there is a common need for a thorough understanding of HA's microscopic structure and functions, particularly including mechanical properties and their relation to the ionic effects that dominate osmotic and viscoelastic properties. With the prior NSF project, this researcher has established that low-force single-molecule elasticity measurements are powerful tools to understand polyelectrolyte structure in complex solutions. Here, 'low force' means tensions small enough to permit looped, random-walk structure in the chain; such forces are inaccessible to standard force spectroscopy approaches that only access nearly-straight chain configurations. Low forces permit sensitivity to weak, long range interactions, and thus quantification of the effects that are key to HA's biological and biomaterials functions, such as electrostatic repulsion, direct and water-mediated hydrogen bonding, and self-avoidance. Here, the proposed studies are to apply the low-force approach to a rigorous examination of HA's solution-mediated conformational and mechanical properties. This research will proceed through the following two goals. In goal 1, HA conformation will be studied as modulated by electrostatic screening, water structure (using chao/kosmotropic salts), and in the presence of crowders. In goal 2, the effects of specific biological ligands on HA conformation will be studied, with emphasis on proteogylcans that cause swelling and crosslinking effects. International dissemination and scientific exchange that are unique and important in the context of achieving broader impact of the sciences are part of this awards.

非技术性：该奖项由加州大学圣塔芭芭拉分校材料研究部生物材料项目颁发，旨在研究透明质酸（透明质酸，HA）在盐和其他与该聚合物结合的分子存在的情况下的尺寸、形状和溶液特性。透明质酸或透明质酸 (HA) 是一种巨大的聚合物分子，它定义了人体许多空间的结构和力学，例如组织水合、伤口愈合、某些生物界面的润滑，并有助于定义关节的力学和功能。此外，HA 正在积极研究用于生物材料应用，特别是用作细胞/组织工程基质的功能化 HA 凝胶。 HA 的这些功能依赖于其聚合的随机游走结构，该结构受到溶液条件的调节，包括盐浓度、其他生物聚合物的拥挤以及 HA 结合分子的存在。因此，出于生物学和化学原因，详细了解 HA 构象和溶液行为的微观基础具有重要意义。拟议的研究预计将有助于更好地了解 HA 的各种生物学作用，并允许对基于 HA 的生物材料进行合理的工程设计。此外，开展该项目将产生各种重要的更广泛的影响，包括加强大学/国家实验室的伙伴关系，以及在具有良好长期潜力的跨学科科学领域培养本科生和研究生的年轻科学家。国际传播和科学交流是该项目的一部分，这些独特的活动对于实现更广泛的科学影响非常重要。技术：透明质酸（HA）是一种多糖，几乎存在于所有哺乳动物组织中。 HA 的特点是阴离子电荷密度大、构象灵活性以及由于各种氢键相互作用而产生的多态性。这些特征及其与某些配体的关联使其定义了细胞外空间（例如细胞周基质、眼睛玻璃体和滑液）的机械和粘弹性特性。 HA 对于临床应用以及作为用于制造细胞和组织生长的凝胶基质的生物材料也更感兴趣。在所有这些生物和生物材料应用中，普遍需要彻底了解透明质酸的微观结构和功能，特别是机械性能及其与主导渗透和粘弹性的离子效应的关系。通过之前的 NSF 项目，该研究人员已经确定低力单分子弹性测量是了解复杂溶液中聚电解质结构的强大工具。这里，“低力”是指张力小到足以允许链条中形成环状、随机游走结构；这种力是标准力谱方法无法获得的，而标准力谱方法只能获得近乎直链的配置。低力允许对弱的长程相互作用敏感，从而量化HA的生物和生物材料功能的关键效应，例如静电排斥、直接和水介导的氢键以及自我回避。在这里，拟议的研究是应用低力方法来严格检查 HA 的溶液介导的构象和机械性能。本研究将通过以下两个目标进行。在目标 1 中，将研究静电屏蔽、水结构（使用混沌/亲液盐）以及拥挤器存在下的调节的 HA 构象。在目标 2 中，将研究特定生物配体对 HA 构象的影响，重点是引起膨胀和交联效应的蛋白聚糖。 在实现更广泛的科学影响的背景下，国际传播和科学交流是独特且重要的，这是该奖项的一部分。