The vertebrate lung develops via a process known as branching morphogenesis, wherein subgroups of epithelial cells are instructed reiteratively to form clefts or buds and thereby generate a space-filling tree with a sufficient surface area for gas exchange to support breathing after birth. An aberrant mechanical environment within the thoracic cavity can disrupt branching and cause fetal pulmonary hypoplasia, a major cause of respiratory insufficiency of the newborn. It is unclear how mechanical stresses control or disrupt the branching program. Here, we describe experiments combining tissue engineering approaches with investigations of intact embryonic lungs to define how mechanical stresses are transduced into gene expression changes that drive branching morphogenesis. Engineered lung tissues and computational models will be used to predict the role of mechanical stresses in branch site initiation.
In Specific Aim 1, we will determine whether and how mechanical stresses regulate branching morphogenesis of engineered embryonic mouse lung tissues and intact chick and mouse embryonic lungs.
In Specific Aim 2, we will define the mechanically induced gene expression changes that drive lung branching. To our knowledge, this work will represent the first comprehensive analysis of mechanically responsive genes in branching morphogenesis in culture or in vivo. We expect that the gene expression patterns revealed will uncover new avenues to explore for medical treatment of mechanically-induced diseases such as fetal pulmonary hypoplasia.

Public Health Relevance

Organ development requires exquisite control processes to ensure proper patterning and generation of functional forms. Increasing evidence suggests that mechanical stresses are involved in the development of the branching patterns of the lung and other tree-like organs, and that aberrant mechanical stresses can cause human fetal pulmonary diseases. We present here an integrated approach to define precisely how mechanical stresses are converted into gene expression changes that drive branching morphogenesis of embryonic lung tissues, which will enable future studies to treat human fetal pulmonary disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL110335-02
Application #
8278596
Study Section
Special Emphasis Panel (ZRG1-CB-P (55))
Program Officer
Lin, Sara
Project Start
2011-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$201,250
Indirect Cost
$76,250
Name
Princeton University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
Varner, Victor D; Nelson, Celeste M (2014) Toward the directed self-assembly of engineered tissues. Annu Rev Chem Biomol Eng 5:507-26
Lee, KangAe; Nelson, Celeste M (2014) Determining the role of matrix compliance in the differentiation of mammary stem cells. Methods Mol Biol 1202:79-94
Jakus, Zoltán; Gleghorn, Jason P; Enis, David R et al. (2014) Lymphatic function is required prenatally for lung inflation at birth. J Exp Med 211:815-26
Chen, Qike K; Lee, KangAe; Radisky, Derek C et al. (2013) Extracellular matrix proteins regulate epithelial-mesenchymal transition in mammary epithelial cells. Differentiation 86:126-32
Gleghorn, Jason P; Manivannan, Sriram; Nelson, Celeste M (2013) Quantitative approaches to uncover physical mechanisms of tissue morphogenesis. Curr Opin Biotechnol 24:954-61
Varner, Victor D; Nelson, Celeste M (2013) Let's push things forward: disruptive technologies and the mechanics of tissue assembly. Integr Biol (Camb) 5:1162-73
Zhu, Wenting; Nelson, Celeste M (2013) PI3K regulates branch initiation and extension of cultured mammary epithelia via Akt and Rac1 respectively. Dev Biol 379:235-45
Kim, Hye Young; Varner, Victor D; Nelson, Celeste M (2013) Apical constriction initiates new bud formation during monopodial branching of the embryonic chicken lung. Development 140:3146-55
Chung, Jae Woo; Lee, KangAe; Neikirk, Colin et al. (2012) Photoresponsive coumarin-stabilized polymeric nanoparticles as a detectable drug carrier. Small 8:1693-700
Zhu, Wenting; Nelson, Celeste M (2012) PI3K signaling in the regulation of branching morphogenesis. Biosystems 109:403-11

Showing the most recent 10 out of 12 publications