Asthma is a serious pulmonary disease that is characterized by airway hyper-responsiveness (AHR), airway remodeling, mucus hyper-secretion and airway inflammation. There is considerable information about the pathogenesis of mucus hyper-secretion and airway inflammation. Our knowledge regarding mechanisms of AHR and airway remodeling is limited. Previous studies show that contraction of airway smooth muscle plays a critical role in mediating AHR whereas proliferation of airway smooth muscle cells largely contributes to the pathogenesis of airway remodeling. However, the mechanisms that regulate airway smooth muscle contraction and growth are not well understood. Abl is a nonreceptor tyrosine kinase that is known to regulate the functions of immune cells by controlling actin polymerization, a cellular process that may also regulate contraction of various smooth muscles including airway smooth muscle. Our pilot studies show that Abl is required for airway smooth muscle contraction and growth, suggesting an important role of Abl in airway smooth muscle. The major goal of the project is to characterize the functional role of Abl in airway smooth muscle in vitro and in allergen-induced AHR and airway remodeling in vivo.
In Aims 1 and 2, the roles and mechanisms of Abl in regulating airway smooth muscle contraction and growth will be characterized.
In Aim 3, the roles of Abl in allergen-induced AHR, airway remodeling and inflammation will be evaluated using an animal model of asthma. Completion of these studies should advance our knowledge regarding smooth muscle contraction/growth and asthma pathology. Obtaining this knowledge may identify Abl as a new biological target for the development of new therapy to treat asthma.

Public Health Relevance

Airway smooth muscle contraction and growth play a critical role in the pathogenesis of airway hyper-responsiveness and airway remodeling. However, the mechanisms that regulate smooth muscle contraction and growth are not well understood. This project is to unveil previously unknown mechanisms that control airway smooth muscle contraction and proliferation using sophisticated technology. Obtaining this knowledge is necessary for the development of new strategies to prevent/treat the disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL113208-03
Application #
8645726
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Banks-Schlegel, Susan P
Project Start
2012-04-15
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
3
Fiscal Year
2014
Total Cost
$348,390
Indirect Cost
$127,890
Name
Albany Medical College
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
190592162
City
Albany
State
NY
Country
United States
Zip Code
12208
Cleary, Rachel A; Wang, Ruping; Waqar, Omar et al. (2014) Role of c-Abl tyrosine kinase in smooth muscle cell migration. Am J Physiol Cell Physiol 306:C753-61
Li, Jia; Chen, Shu; Cleary, Rachel A et al. (2014) Histone deacetylase 8 regulates cortactin deacetylation and contraction in smooth muscle tissues. Am J Physiol Cell Physiol 307:C288-95
Wang, Ruping; Cleary, Rachel A; Wang, Tao et al. (2014) The association of cortactin with profilin-1 is critical for smooth muscle contraction. J Biol Chem 289:14157-69
Chen, Shu; Tang, Dale D (2014) c-Abl tyrosine kinase regulates cytokinesis of human airway smooth muscle cells. Am J Respir Cell Mol Biol 50:1076-83
Wang, Tao; Cleary, Rachel A; Wang, Ruping et al. (2014) Glia maturation factor-? phosphorylation at Tyr-104 regulates actin dynamics and contraction in human airway smooth muscle. Am J Respir Cell Mol Biol 51:652-9
Wang, Tao; Cleary, Rachel A; Wang, Ruping et al. (2013) Role of the adapter protein Abi1 in actin-associated signaling and smooth muscle contraction. J Biol Chem 288:20713-22
Cleary, Rachel A; Wang, Ruping; Wang, Tao et al. (2013) Role of Abl in airway hyperresponsiveness and airway remodeling. Respir Res 14:105
Wang, Ruping; Mercaitis, Orion P; Jia, Li et al. (2013) Raf-1, actin dynamics, and abelson tyrosine kinase in human airway smooth muscle cells. Am J Respir Cell Mol Biol 48:172-8