A precise airway tone is critical for maintaining proper air pressure during inspiration and preventing airway collapse during expiration. Neonates with disorders such as tracheomalacia, a condition where the trachea is floppy, develop breathing difficulties soon after birth. In more common respiratory diseases such as cystic fibrosis, recent studies have revealed that structural defects in the upper airway precede and may contribute to the increased susceptibility to infections. Normal airway tone is achieved through a precise balance of cartilage and smooth muscle that provide the rigidity and elasticity, respectively. In addition, evidence suggests that cartilage and smooth muscle play a key role in maintaining stem cells in the subjacent airway epithelium, and patterning the vasculature and nerves in the surrounding airway mesenchyme. The fundamental questions of how the balance between cartilage and smooth muscle is established, and what their specific roles are as organizers of other tissues in the microenvironment remain poorly understood. We have generated a series of cartilage and smooth muscle mutants, and will use them to test the in vivo requirements of these lineages in homeostasis, responses to airway injury and allergen challenges.

Public Health Relevance

We will investigate how airway cartilage and smooth muscle achieve their juxtaposed pattern which is essential to maintain upper airway tone. Beyond their role as structural components of the airway, we will also investigate how they impact the formation, maintenance and regeneration of adjacent epithelium, vasculature and nerves. Our findings will define how malformation of the airway cartilage and/or smooth muscle in the fetal period can contribute to multiple hallmarks of pulmonary diseases in the adult.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL119946-01A1
Application #
8761412
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Banks-Schlegel, Susan P
Project Start
2014-08-01
Project End
2018-04-30
Budget Start
2014-08-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
$531,260
Indirect Cost
$181,260
Name
University of Wisconsin Madison
Department
Genetics
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715