A Mathematical-Experimental Strategy to Discern the Molecular Basis of "Successful Mucus"

辨别“成功粘液”分子基础的数学实验策略

• 批准号: 1462992
• 负责人: M Forest
• 金额: $ 96万
• 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: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1462992&HistoricalAwards=false
• 关键词: Mathematical; Experimental; Strategy; Discern; Molecular

In human airways, the mucus barrier is the front line of defense whereas the immune system is secondary.  "Successful mucus" efficiently traps invasive cargo (pathogens and particulates) and continuously clears mucus and cargo from the airways to the larynx where it is swallowed to the gut and chemically disarmed before penetration of the mucus barrier, preventing exposure to cells or the blood stream.  Many diseases and pathologies are now associated with "unsuccessful mucus," from genetic diseases like cystic fibrosis to acquired conditions such as chronic obstructive pulmonary disease (COPD).  Mucus has become the miner's canary of lung health.  The experimental-mathematical projects outlined in this research present a strategy to replace quality-of-life metrics of lung disorders with rigorous, robust scientific metrics that integrate novel experimental technique with the mathematics of data analytics, model selection, and predictive computation.  These advances promise a new standard for mucus biology, with the potential to transform clinical practice from patient symptoms to preemptive monitoring and assessment of mucus transport properties, to identification of likely sources of success and failure, and to test impact and duration of therapeutics.  The education and training of undergraduates, graduate students, and postdoctoral scholars in the integration of knowledge and techniques from biology, biophysics, applied mathematics, statistics, and medicine contributes to the enrichment of all disciplines and fields, and furthermore to the future generation of researchers and practitioners in academia and the public and private sector.    Mucus in every organ has a baseline composition (a spectrum of mucin macromolecules, proteins, electrolytes, and water) that is reproducible in cell cultures, and then a host of "living-induced" molecular species (pathogens and by-products, immune response agents, DNA from dead cells, and substances from environmental and lifestyle factors).  This molecular composition conveys to healthy mucus the ability to impede the diffusion of species from nanometer to micron size, and the ability to be activated (thereby cleared) down to pico-Newton forces of single cilia.  All particles tracked via microscopy in mucus diffuse "non-normally" and the statistics of their diffusion varies with particle size and surface chemistry; all rheology data point to nonlinear viscoelastic behavior that differs depending on the frequency, lengthscale, and stress level of the propulsion mechanisms in the lung.  This striking capacity of successful mucus to respond simultaneously yet differently to the diversity of insults and to its clearance by cilia and air drag has confounded the science of mucus biology.  Consequently, there has been no assessment standard of transport properties for mucus, no conclusive test for successful mucus, no understanding of what molecular species or tandem species determine mucus success or failure in either transport property, and no rigorous basis to test potential remedies to reinstate healthy transport properties.  In this project, experimental techniques will be explored to decompose mucus with respect to its molecular basis, with top-down deconstruction of clinical mucus into baseline and living-induced components, and bottom-up reconstruction from a sterile cell culture baseline superimposed with controlled living-induced components.  Mathematical techniques will be developed to assess diffusive and viscoelastic properties of physiological relevance over this entire mucus sample space, including strategies to resolve open mathematical questions about anomalous diffusion and nonlinear viscoelasticity.

在人类呼吸道中，粘液屏障是第一道防线，而“成功的粘液”是次要的，可以有效地捕获侵入性物质（病原体和颗粒物），并持续清除呼吸道中的粘液和物质，并被吞咽到喉部。在穿透粘液屏障之前，肠道会被化学解除武装，从而防止暴露于细胞或血流中，现在许多疾病和病理都与“不成功的粘液”有关。囊性纤维化等遗传性疾病以及慢性阻塞性肺病 (COPD) 等后天性疾病已成为矿工肺部健康的金丝雀。本研究中概述的实验数学项目提出了一种替代肺部生活质量指标的策略。这些进步为粘液生物学提供了新的标准，有可能将临床实践从患者症状转变为疾病。预先监测和评估粘液运输特性，确定成功和失败的可能来源，并测试治疗的影响和持续时间对本科生、研究生和博士后学者进行生物学知识和技术整合的教育和培训。 、生物物理学、应用数学、统计学和医学有助于丰富所有学科和领域，此外还有助于学术界以及公共和私营部门的下一代研究人员和从业者​每个器官的粘液都有一个基线成分。 （一系列粘蛋白大分子、蛋白质、电解质和水）可在细胞培养物中复制，然后是大量“活诱导”分子种类（病原体和副产品、免疫反应剂、死细胞的 DNA 和这种分子组合物向健康的粘液传递了阻止从纳米到微米大小的物质扩散的能力，以及被激活（从而清除）到皮牛顿力的能力。通过显微镜追踪的所有颗粒在粘液中“非正常”扩散，并且其扩散的统计数据随颗粒尺寸和表面化学变化而变化；所有流变学数据都表明非线性粘弹性行为随频率、长度尺度和应力水平的不同而变化。成功的粘液对各种损伤以及纤毛和空气阻力的清除做出不同反应的惊人能力同时混淆了粘液生物学科学。测试中，没有粘液传输特性的评估标准，没有成功粘液的结论性测试，不了解哪些分子种类或串联种类决定粘液传输特性的成功或失败，也没有严格的基础来测试恢复潜在补救措施在该项目中，将探索实验技术来分解粘液的分子基础，将临床粘液自上而下地解构为基线和活体诱导成分，并从无菌细胞培养基线进行自下而上的重建。叠加有将开发数学技术来评估整个粘液样本空间的生理相关性的扩散和粘弹性特性，包括解决有关异常扩散和非线性粘弹性的开放数学问题的策略。