Embryonic lung development is a poorly understood process involving the coordination of cellular growth and organization to give rise to functional airways that are critical for survival. Recently, contractions of the smooth muscle that surrounds the developing airways was discovered to have a critical role in the branching of new airways during embryonic development. Two types of smooth muscle contractions - fast and slow - occur in the developing lung. This research will determine the connection between fast and slow airway smooth muscle contractions, their role in airway branching, and the cellular activity underlying these processes. Deeper understanding of the mechanisms that cause the growth of the airways is of importance for understanding lung development in general and also for predicting, preventing, and repairing structural birth defects. The methods created in this research to study lung development could have application to development of other organs where muscular contractions change development. This project will offer a basis for undergraduate and graduate training in the mechanics of development and serve to engage and inspire students in the STEM fields with the creation of modules and lesson plans for dissemination to secondary schools about microfluidic approaches to treat disease.
Spatially uncoordinated, fast peristaltic contractions and newly identified, coordinated slow contractions of the airway smooth muscle are both active in the lung and regulated by the fluid pressure within the airways. This work focuses on documenting the kinetics of airway smooth muscle contractions across multiple time and length scales and developing an understanding of its molecular regulators. To explore these events and the underlying molecular mechanisms, the objectives of this project are: (1) use video microscopy to characterize the multi-timescale contraction kinetics; (2) determine the role of contractile proteins ex vivo, utilizing immunohistochemical and adenoviral techniques; and, (3) determine the role of mechanics on inducing contraction events, utilizing a newly developed microfluidic smooth muscle in vitro platform. By understanding these developmental mechanisms, we can use them as tools to guide de novo production of tissue for regenerative medicine and enable future studies interrogating the role of specific genetic and/or structural factors.
