The flow of liquid by beating cilia is ubiquitous in human physiology. The failure of cilia-induced fluid flow in the lungs (mucociliary clearance), as in Cystic Fibrosis, primary cilia dyskinesis, and environmentally damaged lungs, leads to severe health problems as the lung tissue is destroyed by infections that cannot be cleared. Significant progress has been made in recent years in identifying the key genetic muta-tion responsible for Cystic Fibrosis, studying the hydrodynamics and biochemistry and the beginning of effective treatments. In parallel, strides in theory and simulation have begun to tackle issues such as the basis for force production in biological molecules, the rheology of biological fluids and hydrodynamics of viscous, complex flows. We believe that we stand at a critical time when an understanding of biological systems codified into a unified simulation is essential for making breakthroughs in the science of micro-biological hydrodynamics. Our vision is a cross disciplinary research effort that will study mucociliary clearance as a case study in biological flows from the consequences of genetic mutations and biochemical networks up to the scale of macroscopic hydrodynamics. By combining a team of researchers from Applied Mathematics, Computer Science, Chemistry, Physics and Astronomy, Biochemistry and Biophysics, and the Cystic Fibrosis Center, our long term goal is to develop an integrated computational model that will be able to predict and evaluate truly effective therapeutic strategies.

AIM 1: What is the Airway Surface Liquid?

The liquid layer between the epithelial tissue and the air is understood to be a two fluid system, with a mucus layer riding on the periciliary liquid (PCL). We need to understand their chemical and physical properties and the consequences for hydrodynamics.

• Project 1: Mucus Composition, Structure, Rheology – We will identify the molecular composition , structure, network and rheological properties of the mucus gel from purified fractions and within human lung cell cultures. A model of the network properties and rheology of the mucus will be developed.
• Project 2: Periciliar Liquid (PCL) Composition, Structure, Rheology –We will extract PCL from cell cultures for compositional analysis while focusing most of our effort in characterizing the rheology of the PCL within the cell culture using FRAP and microbead rheology.
• Project 3: Mucus PCL Phase Separation – Does the mucus/PCL system constitute a sol/gel system? Why is the PCL depth equal to the cilia length? We will develop a theoretical model of polymer phase separation due to geometrical and chemical boundaries, tested against physical models and cell cultures.
• Project 4: Mucus Adhesion – When the PCL is depleted the mucus layer collapses onto the cilia where it adheres. The release of the mucus is a major therapeutic challenge. We will develop models of poly-mer/polymer intertwining complemented by adhesion measurements on model systems an dcell cultures.

AIM 2: Why does the Airway Surface Liquid move?

The flow of mucus is driven principally by cilia and by airflow. We need to understand how the mechanism of transport works in healthy systems and is compromised by disease.

• Project 5: Cilia Forces and Mechanoresponse – We will develop a multiscale model of axoneme dy-namics starting from the scale of a stochastic model of dynein to the scale of the cilia. Model development will be informed by direct measurements of force generation in live human lung cell cultures.
• Project 6: Cilia Induced Flow Dynamics: We will model the coupling between the cilia and the sur-rounding liquid (PCL and mucus) including the effects of the mucus rheology as a viscoelastic medium. Complex hydrodynamics such as mixing will be included, complemented by high speed tracer imaging.
• Project 7: Air Induced Flow Dynamics: Cough is highly effective at stimulating mucus clearance both through physical means and through triggering biochemical responses. We will model the high speed air-flow over the mucus complemented by experiments performed on cell cultures and model systems.

AIM 3: Large Scale Model Development

Modeling extends throughout each of the projects in close coordination with experiments. Indeed, it is the development of the models that specifies the experiments to be performed. Our long range goal, the unifi-cation of all models. will begin immediately with the parallel development of three integrated models.

• Project 8: Biochemical Networks: We will develop a hierarchical series of biochemical networks that increase in scope and complexity during the project. We will successively model nucleotide chemistry, ion transport, mucin secretion and cilia control.
• Project 9: Simulation Integration: The methodology of integrating numerical models that operate on different space and time mesh sizes, different execution times, languages and computer hardware is a challenging task. We will develop connection strategies that merge codes with a transparency that allows individual modules to be developed while maintaining the robustness of the integrated model.