Dynamic tuning of barrier properties of biogels using weakly adhesive third-party crosslinkers

使用弱粘合性第三方交联剂动态调节生物凝胶的阻隔性能

• 批准号: 1810168
• 负责人: Samuel Lai
• 金额: $ 50.17万
• 依托单位: University of North Carolina at Chapel Hill
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1810168&HistoricalAwards=false
• 关键词: Dynamic; tuning; barrier; properties; biogels

Non-Technical AbstractHydrogels, composed of a network of fibers suspended in an aqueous environment, are ubiquitous in living systems. Hydrogels not only offer unique structural and mechanical properties essential for numerous physiological functions, but also serve as a barrier against foreign species. Current methods to tune the ability of biological hydrogels (biogels) to function as a physical barrier typically rely on either changing the spacing between the fibers, or by tuning the molecular composition of the fibers. However, both methods have important limitations. Here, we would explore the use of third-party molecules that can crosslink foreign species to the matrix by binding tightly to the foreign species while binding lightly to the matrix fibers. We will study a variety of biogels to identify the specific molecules that the crosslinkers can bind to on the fibers. We will also explore improving the potency of the crosslinkers by tuning its interactions with the fibers and/or its ability to crosslink foreign species. Finally, we will develop mathematical theory and computational model that can account for the experimental observations. Altogether, these studies should help us substantially advance a novel approach to changing the effectiveness of biogels to serve as a barrier.Technical AbstractCurrent methods to tune the barrier properties of biological hydrogels (biogels) typically involve either stimuli-induced bulk changes to the mesh spacings of the matrix, and/or covalent modification of the matrix elements. These methods greatly limit the ability to dynamically tune the barrier properties of biogels against diverse species. In this proposal, we will elucidate a third strategy, based on harnessing adaptive third-party crosslinkers that can interact weakly with matrix elements and bind specifically to foreign epitopes to tune the barrier properties of biogels against nano-sized particles and active bodies with molecular specificity. In particular, we will focus on utilizing antibodies (Ab), which we have recently discovered can interact transiently with mucins and laminin via N-glycans on its Fc domain, as model third party crosslinkers. In Aim 1, we will explore the interactions of Ab with a variety of biogels; the systemic screening will allow us to gain molecular insights into the specific elements on biogel matrix that mediate the interactions with Ab. In Aim 2, we will explore whether tuning Ab affinity to matrix constituents, or improving the ability of Ab to agglutinate, will result in more effective immobilizing of active species in biogels. Finally, in Aim 3, we will develop a comprehensive theoretical framework and computational model of the experimental observations. Successful completion of the proposed studies will substantially improve our understanding of this novel strategy to tune the barrier properties of biogels.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.

水凝胶由悬浮在水环境中的纤维网络组成，在生命系统中普遍存在。 水凝胶不仅提供了许多生理功能所必需的独特结构和机械性能，而且还可以作为抵御外来物种的屏障。 目前调节生物水凝胶（凝胶）作为物理屏障的能力的方法通常依赖于改变纤维之间的间距，或者通过调节纤维的分子组成。 然而，这两种方法都有很大的局限性。 在这里，我们将探索第三方分子的使用，该第三方分子可以通过与外来物质紧密结合而与基质纤维轻微结合来将外来物质交联到基质上。 我们将研究各种纤维素，以确定交联剂可以在纤维上结合的特定分子。 我们还将探索通过调整其与纤维的相互作用和/或其交联外来物质的能力来提高交联剂的效力。 最后，我们将开发数学理论和计算模型，可以解释实验观察。 总之，这些研究应该帮助我们大大推进一种新的方法来改变的有效性的生物凝胶作为barrier.Technical AbstractCurrent的方法来调整生物水凝胶（生物凝胶）的阻隔性能通常涉及刺激诱导的散装变化的网格间距的矩阵，和/或共价修饰的矩阵元素。 这些方法极大地限制了动态调节生物胶对不同物种的阻隔性能的能力。 在这项提案中，我们将阐明第三种策略，该策略基于利用自适应第三方交联剂，该交联剂可以与基质元素弱相互作用，并特异性地结合外源表位，以调整生物素对纳米颗粒和具有分子特异性的活性体的屏障特性。 特别是，我们将重点利用抗体（Ab），我们最近发现可以通过其Fc结构域上的N-聚糖与粘蛋白和层粘连蛋白瞬时相互作用，作为模型第三方交联剂。 在目标1中，我们将探索抗体与各种抗体的相互作用;系统筛选将使我们能够获得对抗体基质上介导与抗体相互作用的特定元素的分子见解。 在目标2中，我们将探讨是否调整抗体的亲和力，基质成分，或提高抗体凝集的能力，将导致更有效的固定活性物质在凝胶。 最后，在目标3中，我们将开发一个全面的理论框架和实验观测的计算模型。 成功完成拟议的研究将大大提高我们对这一新战略的理解，以调整的屏障性能的martels.This奖项反映了NSF的法定使命，并已被认为是值得的支持，通过评估使用基金会的知识价值和更广泛的影响审查标准。

项目成果

Limited processivity of single motors improves overall transport flux of self-assembled motor-cargo complexes

单个电机的有限加工能力提高了自组装汽车货运综合体的整体运输通量

• DOI: 10.1103/physreve.100.022408
• 发表时间: 2019
• 期刊: Physical Review E
• 影响因子: 2.4
• 作者: Patel, Keshav B.;Mao, Shengtan;Forest, M. Gregory;Lai, Samuel K.;Newby, Jay M.
• 通讯作者: Newby, Jay M.

Robust antigen-specific tuning of the nanoscale barrier properties of biogels using matrix-associating IgG and IgM antibodies

使用基质相关 IgG 和 IgM 抗体对生物凝胶的纳米级屏障特性进行稳健的抗原特异性调节

• DOI: 10.1016/j.actbio.2019.03.023
• 发表时间: 2019
• 期刊: Acta Biomaterialia
• 影响因子: 9.7
• 作者: Schiller, Jennifer L.;Marvin, Allison;McCallen, Justin D.;Lai, Samuel K.
• 通讯作者: Lai, Samuel K.

Modeling Barrier Properties of Intestinal Mucus Reinforced with IgG and Secretory IgA against Motile Bacteria

• DOI: 10.1021/acsinfecdis.9b00109
• 发表时间: 2019-09-01
• 期刊: ACS INFECTIOUS DISEASES
• 影响因子: 5.3
• 作者: Xu，Feifei;Newby，Jay M.;Lai，Samuel K.
• 通讯作者: Lai，Samuel K.