(3hy) A Breathable Barrier: Modeling and Modulating Biophysics and Transport Processes at the Airway Surface

Research Interests: While the alveoli of the distal lung function primarily as a gas exchange membrane, the conducting airways that allow passage of inhaled air and exhaled waste gas are the body’s primary barrier to inhaled airborne particles and pathogens. The airway surface liquid (ASL) layer is complex system of active and passive transport processes at multiple spatiotemporal scales divided into two primary compartments: the mucus layer and the pericilium-glycocalyx (PCL-G). The airway mucus layer is a biopolymeric hydrogel composed of the two gel-forming mucins MUC5B and MUC5AC and other biomacromolecules. The sticky mucus network traps inhaled particles and pathogens and yet is biophysically tuned to allow for vertical mucociliary clearance (MCC) out of the lungs by the synchronized beating of the hair-like cilia that line the airways. The cilia and bottle-brush glycoproteins that decorate them and the epithelial cell surface form an even finer molecular exclusion barrier than the mucus while allowing for liquid and ion transport to maintain the mucus layer in a state of physiological hydration for functional clearance. Dysfunction in and pathogenic exploitation of the individual components of this ASL system cause multiple acute and chronic diseases that affect hundreds of millions of people globally. Inhaled treatments, if engineered to enhance or evade these defenses, could be used to treat those and millions of others with chronic and acute diseases both locally and systemically.

My research-to-date has focused primarily on the airway mucosal defects present in cystic fibrosis (CF), a disease where deficient chloride secretion causes mucus hyperconcentration and obstruction of the airways and other mucosal tissues (e.g. the gut and pancreas). However, the biochemical and biophysical lessons learned from studying the ASL, and particularly the mucus, in CF necessarily illuminate the physiology of transport in and of healthy mucus as well as in other diseases like COPD (i.e. chronic bronchitis), asthma, and idiopathic pulmonary fibrosis (IPF). My research has been and will remain essentially translational, focusing not just on physiology and pathophysiology, but on generating effective treatments and treatment strategies using physical modeling and systems biology/systems medicine tools. Ultimately, I envision establishing a research laboratory that uses fundamental understanding of the biochemistry and biophysical transport of particles and pathogens in mucus and of mucus itself to develop pharmacokinetic-pharmacodynamic models of therapeutic delivery for both airway and systemic disease.

Training History:

Ph.D. in Chemical Engineering, University of Pittsburgh - Advisors: Robert S. Parker and Timothy E. Corcoran (2017).

My dissertation, “Multiscale mathematical modeling of the absorptive and mucociliary pathophysiology of cystic fibrosis lung disease”, focused on generating cell- and lung-scale models of the CF ASL and MCC transport in in vitro and in vivo contexts, respectively. Both models were informed by modeling the active and passive absorption of radiopharmaceutical probes and provided a mechanistic means to demonstrate and explain the efficacy of inhaled hypertonic saline in reducing ASL hyperabsorption and improving MCC in patients with CF. The cell-scale model further predicted that non-ionic osmolytes such as mannitol would provide more sustained treatment than hypertonic saline, a prediction which has since been validated.

Postdoctoral Research Fellow, University of North Carolina – Advisor: David B. Hill (Current)

My postdoctoral work has focused on the biophysics of airway mucus in CF and other diseases and chemical means by which to decrease the viscoelasticity of mucus in those diseases. Both at UNC and in an international collaboration with researchers in the Australian Respiratory Early Surveillance Team for CF (AREST CF) I have applied mathematical modeling to identify biophysical (i.e. microrheological) signals of mucopathy in dilute patient airway samples retrieved via bronchoalveolar lavage. Additionally, we have demonstrated the efficacy of thiol mucolytics in reducing the complex viscosity of mucus in multiple disease states including CF and IPF. Recently, I have added a focus toward generating tunable mucus “stocks” that have physiological properties for the study of mucus biochemistry and modeling of pathogen transport and disease.

Teaching Experience and Interests: I am highly motivated to teach future generations of chemical engineers. As part of my training as a GAANN Fellow during my doctoral studies I was a full co-instructor of the Reactive Process Engineering course for junior-level undergraduates. I also served twice as teaching assistant of the Systems Engineering 1: Dynamics and Modeling for senior level undergraduates and once for the Introduction to Engineering Computing Class for first-semester freshmen. Furthermore, I have published two manuscripts and a chapter of my dissertation on the effects of virtual internships on entrepreneurship in engineering students under the mentorship of Cheryl Bodnar (now at Rowan University).

I am confident in my ability to teach any core class in a chemical engineering undergraduate curriculum. I have an affinity for teaching a kinetics/reactive process design course or a process dynamics and control course. I would also be enthusiastic to instruct graduate level modeling and control, systems biology, or drug design and delivery courses. I am more than happy to teach any course mentioned above in a biological context, as my undergraduate education at the University of Colorado was structured in that manner. I enjoy mentoring undergraduates in research, having mentored 8 total: 6 during my doctoral work and 2 during my postdoctoral studies.

Successful Proposals:

Cystic Fibrosis Foundation Postdoctoral Research Fellowship (2018-present)

• $60,300 per year for salary and supplies for 2 years
• Successfully reapplied for 3^rd year of funding

Horton Family Young Investigator in Cystic Fibrosis Award (2018-19)

• One-time $30,000 research fund for junior researcher in cystic fibrosis

Selected Publications (Main Author): Full list of publications on my Google Scholar profile

Markovetz, M.R., Subramani, D.B., Kissner, W.J., Morrison, C.B. et al. “Endotracheal Tube Mucus as a Source of Airway Mucus for Rheological Study.” American Journal of Physiology-Lung Cellular and Molecular Physiology. 2019.

Markovetz, M.R., Corcoran, T.E., Locke, L.W., Myerburg, M.M., Pilewski, J.M. and Parker, R.S., “A physiologically-motivated compartment-based model of the effect of inhaled hypertonic saline on mucociliary clearance and liquid transport in cystic fibrosis.” PloS one, 9(11), p.e111972. 2014.

Markovetz, M.R., Clark, R.M., Swiecki, Z., Irgens, G.A., Chesler, N.C., Shaffer, D.W. and Bodnar, C.A., “Influence of End Customer Exposure on Product Design within an Epistemic Game Environment.” Advances in Engineering Education, 6(2), p.n2. 2017

Markovetz, M.R., Garbarine I.C., Kissner, W.J., Seim, I., Forest, M.G., Esther Jr., C.R., Muhlebach, M.S., Boucher, R.C., and Hill, D.B. "Increased Airway Mucus Viscoelasticity is Associated with Positive Culture for Pathogens in Cystic Fibrosis Bronchioalveolar Lavage Fluid." Journal of Clinical Investigation: in preparation