In silico evaluation and exploration of antibiotic tuberculosis treatment regimens

Submitted by kirschne on

Background

Improvement in tuberculosis treatment regimens requires selection of antibiotics and dosing schedules from a large design space of possibilities. Incomplete knowledge of antibiotic and host immune dynamics in tuberculosis granulomas impacts clinical trial design and success, and variations among clinical trials hamper side-by-side comparison of regimens. Our objective is to systematically evaluate the efficacy of isoniazid and rifampin regimens, and identify modifications to these antibiotics that improve treatment outcomes.

Digital Lung

What is being modeled?
Pulmonary gas flow, lung tissue, heat and mass transfer, epithelial cell functions for airway surface liquid regulation by mechanical forces
Description & purpose of resource

The lung model integrates mechanics and cell models. The mechanics model utilizes imaging-based, high-fidelity computational technologies for three-dimensional (3D) fluid and solid mechanical systems to predict airflow-induced shear stress, tissue stress and particle deposition at a local level in the realistic human lung models. The cell model is based upon mathematical cell biology and in vitro data for epithelial cells and nucleotide metabolism to predict adenosine triphosphate nucleotide (ATP) release, cell metabolism, ion and water transport, periciliary liquid (PCL) height, and calcium ion concentration [Ca2+].

The broad objective of this research is to apply the above model to study the mechanical force resulting from the multiscale interactions between pulmonary gas flow and lung tissue mechanics, and its role in the distribution and progression of lung disease. A driving biological hypothesis providing one motivation for this work is that lung diseases alter mechanical force, which then alters stress-mediated ATP release, disturbs PCL water homeostasis, and weakens the integrated airway defense system, forming a vicious cycle of events.

Spatial scales
molecular
cellular
tissue
organ
Temporal scales
<10-6 s (chemical reactions)
1 - 103 s
This resource is currently
mature and useful in ongoing research
Key publications (e.g. describing or using resource)

Lin, C.-L., M.H. Tawhai, E.A. Hoffman. Multiscale image-based modeling and simulation of gas flow and particle transport in the human lungs. Wiley Interdiscip Rev Syst Biol Med. 2013;5(5):643-55. 

Jahani, N., S. Choi, J. Choi, K. Lyer, E.A. Hoffman, and C.-L. Lin. Assessment of Regional Ventilation and Deformation Using 4D-CT Imaging for Healthy Human Lungs during Tidal Breathing. J. Applied Physiology, 2015; 119(10):1064-1074.

Wu, D., S. Miyawaki, M.H. Tawhai, E.A. Hoffman, C.-L. Lin. A numerical study of water loss rate distributions in MDCT-based human airway models. Annals of Biomedical Engineering. 2015;43(11):2708-21.

Miyawaki, S., S. Choi, E.A. Hoffman, C.-L. Lin. A 4DCT imaging-based breathing lung model with relative hysteresis. Journal of Computational Physics. 2016;326:76-90.

Miyawaki, S, M.H. Tawhai, E.A. Hoffman, S.E. Wenzel, C.-L. Lin. Automatic construction of subject-specific human airway geometry including trifurcations based on a CT-segmented airway skeleton and surface. Biomechanics and Modeling in Mechanobiology. 2016:1-14.

Wu, D., R. C. Boucher, B. Button, T. Elston, C.-L. Lin. An Integrated Mathematical Epithelial Cell Model for Airway Surface Liquid Regulation by Mechanical Forces, Journal of Theoretical Biology, 2018; 438: 34-45.

DOI link to publication describing this resource

https://doi.org/10.1002/wsbm.1234

https://doi.org/10.1152/japplphysiol.00339.2015

https://doi.org/10.1007/s10439-015-1318-3

https://doi.org/10.1016/j.jcp.2016.08.039

https://doi.org/10.1007/s10237-016-0838-6

https://doi.org/10.1016/j.jtbi.2017.11.010

 

Collaborators
Ching-Long Lin
PI contact information
ching-long-lin@uiowa.edu
Keywords
computational fluid dynamics
image registration
computed tomography
Lung model
parallel computing
Table sorting checkbox
Off

A Multi-scale Approach to Designing Therapeutics for Tuberculosis

Submitted by kirschne on

Approximately one third of the world's population is infected with Mycobacterium tuberculosis. Limited information about how the immune system fights M. tuberculosis and what constitutes protection from the bacteria impact our ability to develop effective therapies for tuberculosis. We present an in vivo systems biology approach that integrates data from multiple model systems and over multiple length and time scales into a comprehensive multi-scale and multi-compartment view of the in vivo immune response to M. tuberculosis.

A systems pharmacology approach towards the design of inhaled formulations of rifampicin and isoniazid for treatment of tuberculosis

Submitted by kirschne on

Conventional oral therapies for the treatment of tuberculosis are limited by poor antibiotic distribution in granulomas, which contributes to lengthy treatment regimens and inadequate bacterial sterilization. Inhaled formulations are a promising strategy to increase antibiotic efficacy and reduce dose frequency. We develop a multiscale computational approach that accounts for simultaneous dynamics of a lung granuloma, carrier release kinetics, pharmacokinetics, and pharmacodynamics.

Subscribe to