A Mathematical-Experimental Strategy to Discern the Molecular Basis of (Un)Successful Mucus

Research project

Description

The mucus barrier is the front line of defense in every organ not covered by skin. Sussessful
mucus traps invasive cargo(pathogens, particulates, and chemical insults) and continuously
clears mucus and cargo prior to exposure to cells or vasculature. Thus the "success"
of mucus is determined by simultaneous orchestration of two fundamental transport processes,
diffusion and flow, and their relative timescales. Many diseases and pathologies are now associated with unsuccessful mucus, compelling a means to assess both transport properties, to discern sources of success and failure, and to test impact and duration of treatments. This would be simple if mucus was a simple viscous fluid, which it is not. Mucus in every organ has a baseline composition (a spectrum of mucin macromolecules, proteins, and electrolytes) 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, environmental, and lifestyle
factors). This molecular composition conveys to healthy mucus the ability to impede diffusion
of species from ten nm to several microns, and to be activated down to pico-Newton forces
of single cilia. All visible tracked particles in mucus diffuse anomalously, and all rheology
data point to nonlinear viscoelastic behavior across the spectrum of physiological frequencies,
forces, and stresses. Consequently, there is no assessment standard of transport properties
for mucus, there is no conclusive test for successful mucus, there is no understanding of
what molecular species or tandem species determine mucus success or failure in either transport property, and no rigorous basis exists to test potential remedies to reinstate healthy transport properties. Experimental techniques are proposed 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 are proposed 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 viscoelasticity.
StatusActive
Effective start/end date9/15/158/31/18

Funding

  • National Science Foundation (NSF)

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Mucus
Cell Culture Techniques
Cilia
Mucins
Electrolytes