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

在人类的呼吸道中，粘液屏障是防御的第一线，而免疫系统是次要的。 “成功的粘液”有效地捕获侵入性货物（病原体和颗粒），并连续地将粘液和货物从气道清除到喉，在喉中，粘液和货物被吞咽到肠道，并在粘液屏障穿透之前被化学解除武装，从而防止暴露于细胞或血流。 许多疾病和病理现在都与“不成功的粘液”有关，从囊性纤维化等遗传性疾病到慢性阻塞性肺病（COPD）等后天性疾病。 粘液已经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策略，将肺部疾病的生活质量指标与严格，强大的科学指标相结合，将新的实验技术与数据分析，模型选择和预测计算的数学相结合。 这些进展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粘液运输特性的抢先监测和评估，识别成功和失败的可能来源，并测试治疗的影响和持续时间。 本科生，研究生和博士后学者在生物学，生物物理学，应用数学，统计学和医学的知识和技术的整合的教育和培训有助于丰富所有学科和领域，并进一步为未来一代的研究人员和从业人员在学术界和公共和私营部门。 每个器官中的粘液都有一个在细胞培养中可重现的基线组成（一系列粘蛋白大分子、蛋白质、电解质和水），然后是一系列“活诱导”分子种类（病原体和副产物、免疫反应剂、死细胞的DNA以及环境和生活方式因素的物质）。 这种分子组成向健康粘液传递阻止物质从纳米扩散到微米尺寸的能力，以及被激活（从而被清除）到单个纤毛的皮牛顿力的能力。 通过粘液中的显微镜跟踪的所有颗粒扩散“非正常”，并且它们的扩散的统计数据随颗粒尺寸和表面化学而变化;所有流变学数据指向非线性粘弹性行为，其取决于肺中推进机制的频率、长度尺度和应力水平而不同。 成功的粘液同时但不同地对各种各样的损伤以及纤毛和空气阻力的清除做出反应的惊人能力使粘液生物学科学感到困惑。 因此，没有粘液运输特性的评估标准，没有成功粘液的结论性测试，不了解什么分子种类或串联种类决定粘液在任一运输特性中的成功或失败，并且没有严格的基础来测试恢复健康运输特性的潜在补救措施。 在该项目中，将探索实验技术，以分解粘液的分子基础，自上而下将临床粘液解构为基线和活性诱导成分，并自下而上从无菌细胞培养基线叠加受控的活性诱导成分进行重建。 将开发数学技术，以评估在整个粘液样本空间的生理相关性的扩散和粘弹性，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。

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.