This Faculty Early Career Development (CAREER) award will focus on better understanding the adverse changes that occur in the arteries of the lung during pulmonary arterial hypertension. This high blood pressure in the pulmonary arteries has a high mortality rate; the only cure is a lung transplant. COVID-19 may also increase the risk of developing this chronic disease. Previous work has shown that accumulation of fibrous tissue in the arteries during disease progression is accompanied by an increase in their mechanical stiffness, which impairs lung blood flow. The specialized cells that synthesize the fibrous matrix of the pulmonary arteries are thought to be stimulated by changes in their mechanical environment. However, the biological mechanisms by which the diseased arteries respond to increased blood pressure and how the structural changes in the vessel wall affect their mechanical properties remain poorly understood. This work will use novel bioengineering measurements and mathematical analysis to improve understanding of the mechanics of disease progression and identify new therapeutic targets. The integration of mathematics, engineering, and biology in this research will also be applicable to other diseases. This research will be complemented with an outreach program that teaches students how skills in biology, mathematics and engineering can be combined to discover solutions to chronic health problems. Undergraduate students will gain hands-on access to the laboratory facilities used in this research.
This research will test the hypothesis that the dynamic changes in pulmonary arterial wall mechanics and extracellular matrix stiffness during pulmonary arterial hypertension impair hemodynamics and regulate adventitial matrix remodeling and stiffening via interactions between profibrotic mechano-signaling pathways. A multiscale approach to this research will integrate experimental and modeling studies by (1) measuring and modeling the time courses of changes in pulmonary arterial hemodynamics, morphology and physiology in vivo in a rat model of the disease; (2) measuring the nonlinear biaxial mechanical properties and structure of arterial tissue and collagen matrix during disease remodeling and use microstructural constitutive models to relate these structural changes to vascular stiffness; and (3) measuring how changes in vessel strain and structural properties regulate profibrotic phenotypes and gene expression and predict them with a mathematical model of the cell regulatory networks.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
