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

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.