CAREER: Biophysical investigations of immune-mediated pathogen trapping in mucus

职业：粘液中免疫介导的病原体捕获的生物物理研究

• 批准号: 1151477
• 负责人: Samuel Lai
• 金额: $ 40万
• 依托单位: University of North Carolina at Chapel Hill
• 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: 2012-04-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1151477&HistoricalAwards=false
• 关键词: CAREER; Biophysical; investigations; immune; mediated

This Career award by the Biomaterials program in the Division of Materials Research to University of North Carolina at Chapel Hill is to investigate the role of mucus, a viscoelastic biopolymer composed of a dense matrix of mucin fibers and secreted by human body, as a barrier against virus. This research project will combine bioengineering, biophysics and computational modeling to investigate the protective role of antibodies in mucus. Most infections are transmitted at mucosal surfaces, and viruses have evolved to readily penetrate mucus. Nevertheless, how antibodies are secreted into mucus protect against infections remain poorly understood. This study is based on the hypothesis that antibodies can immobilize viruses in mucus with permanent avidity via polyvalent and low-affinity crosslinks, thereby blocking viruses from reaching target cells. Most previous studies have failed to detect possible polyvalent-adhesive trapping effects of mucus because these studies attempted to measure only the low-affinity mono-valent interactions between a single antibody and mucus constituents. To overcome these drawbacks of the previous studies, this project will focus on quantifying the potency of anti-biotin immunoglobulin-G mediated trapping by mucus using biotin-coated, mucus-penetrating and mucus-inert polystyrene-based nanoparticles as the model system. Numerical modeling of particle diffusion across mucus, accumulation of antibody on particle surface, and trapping by surface-bound antibody are parts of this research. The proposed studies are expected to develop an overarching set of equations that will attempt to predict the effectiveness of antibody-mediated trapping against a wide range of viral pathogens. In addition, this study could elucidate a largely unrecognized mechanism of immune protection of human body, and could lead to development of new vaccines and passive immunization against viral infections such as Herpes, HIV, etc. Through this multidisciplinary research, graduate and undergraduate students will receive training across nanoscience, biophysics, mathematics and immunology. Additionally, the PI plans to develop a new curriculum, focusing on the role of mucus in health, and will be used by the outreach programs at the Morehead Planetarium and Science Center to reach out to many K-12 students in North Carolina every year.Most infections take place in organs coated with mucus, such as the airways, gastrointestinal tract, etc. Viruses have evolved to quickly move through mucus to infect; thus, methods that can block viruses from penetrating mucus represents an attractive approach to reinforce our body?s defense against infections. In this project, we will explore how the immune system can be tuned to transform mucus into a sticky mesh against diverse pathogens, effectively trapping them in mucus and reducing infections in the process. Specifically, this project will prepare synthetic nanoparticles that will rigorously quantify the stickiness of mucus as a function of basic parameters such as virus particle size and surface characteristics. In addition it will develop an overarching set of equations to predict how one could protect against a wide range of viral pathogens. A successful outcome of this research could not only explain with which immune system can protect against infections, but also could guide in the development of new generations of vaccines. Due to the multidisciplinary nature of this research, the project will train students across nanoscience, biophysics, mathematics and immunology. The researcher plans to leverage existing outreach programs at the Morehead Planetarium and Science Center, and will develop a new science curriculum focusing on the role of mucus in health that will reach many K-12 students in North Carolina. These efforts are expected to motivate students to pursue higher education in Science, Technology, Engineering, & Mathematics.

该职业奖由北卡罗来纳州查佩尔山大学材料研究部生物材料项目授予，旨在研究粘液的作用，粘液是一种粘弹性生物聚合物，由粘蛋白纤维的致密基质组成，由人体分泌，作为抵抗病毒的屏障。本研究项目将结合联合收割机生物工程、生物物理学和计算建模来研究粘液中抗体的保护作用。大多数感染是在粘膜表面传播的，病毒已经进化到很容易穿透粘液。 然而，抗体是如何分泌到粘液中以保护免受感染的仍然知之甚少。 这项研究是基于这样一种假设，即抗体可以通过多价和低亲和力的交联作用，以永久的亲合力将粘液中的病毒包裹起来，从而阻止病毒到达靶细胞。 大多数先前的研究未能检测粘液的可能的多价粘附捕获效应，因为这些研究试图仅测量单个抗体与粘液组分之间的低亲和力单价相互作用。 为了克服以往研究的这些缺点，本项目将集中于使用生物素包被的、粘液穿透的和粘液惰性的基于聚苯乙烯的纳米颗粒作为模型系统来量化粘液介导的抗生物素免疫球蛋白-G的捕获的效力。粒子在粘液中的扩散、抗体在粒子表面的积累以及表面结合抗体的捕获是本研究的一部分。预计拟议的研究将开发一组总体方程，试图预测抗体介导的捕获对各种病毒病原体的有效性。此外，这项研究可以阐明人体免疫保护的一个基本上未被认识的机制，并可能导致开发新的疫苗和被动免疫病毒感染，如疱疹，艾滋病毒等，通过这项多学科的研究，研究生和本科生将接受培训纳米科学，生物物理学，数学和免疫学。 此外，PI计划开发一个新的课程，重点是粘液在健康中的作用，并将用于莫尔黑德天文馆和科学中心的外展计划，以接触北卡罗来纳州每年的许多K-12学生。大多数感染发生在涂有粘液的器官，如气道，胃肠道等。因此，能够阻止病毒穿透粘液的方法是一种很有吸引力的强身方法？这是对感染的防御。 在这个项目中，我们将探索如何调整免疫系统，将粘液转化为针对不同病原体的粘性网，有效地将它们捕获在粘液中，并在此过程中减少感染。 具体而言，该项目将制备合成纳米颗粒，这些纳米颗粒将严格量化粘液的粘性，作为病毒颗粒大小和表面特征等基本参数的函数。 此外，它还将开发一套总体方程，以预测如何预防各种病毒病原体。这项研究的成功结果不仅可以解释免疫系统可以保护免受感染，而且可以指导新一代疫苗的开发。由于这项研究的多学科性质，该项目将培养学生跨纳米科学，生物物理学，数学和免疫学。研究人员计划利用Morehead天文馆和科学中心现有的外展计划，并将开发一个新的科学课程，重点是粘液在健康中的作用，将覆盖北卡罗来纳州的许多K-12学生。这些努力有望激励学生追求科学，技术，工程，数学高等教育。

项目成果

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.

Antibody-Mediated Immobilization of Virions in Mucus

• DOI: 10.1007/s11538-019-00653-6
• 发表时间: 2019-10-01
• 期刊: BULLETIN OF MATHEMATICAL BIOLOGY
• 影响因子: 3.5
• 作者: Jensen, Melanie A.;Wang, Ying-Ying;McKinley, Scott A.
• 通讯作者: McKinley, Scott A.