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 #
5R01HL113208-02
Application #
8458514
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
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$338,436
Indirect Cost
$124,236
Name
Albany Medical College
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
190592162
City
Albany
State
NY
Country
United States
Zip Code
12208
Wang, Yinna; Rezey, Alyssa C; Wang, Ruping et al. (2018) Role and regulation of Abelson tyrosine kinase in Crk-associated substrate/profilin-1 interaction and airway smooth muscle contraction. Respir Res 19:4
Liao, Guoning; Wang, Ruping; Rezey, Alyssa C et al. (2018) MicroRNA miR-509 Regulates ERK1/2, the Vimentin Network, and Focal Adhesions by Targeting Plk1. Sci Rep 8:12635
Tang, Dale D; Gerlach, Brennan D (2017) The roles and regulation of the actin cytoskeleton, intermediate filaments and microtubules in smooth muscle cell migration. Respir Res 18:54
Li, Jia; Wang, Ruping; Gannon, Olivia J et al. (2016) Polo-like Kinase 1 Regulates Vimentin Phosphorylation at Ser-56 and Contraction in Smooth Muscle. J Biol Chem 291:23693-23703
Li, Jia; Wang, Ruping; Tang, Dale D (2016) Vimentin dephosphorylation at ser-56 is regulated by type 1 protein phosphatase in smooth muscle. Respir Res 17:91
Tang, Dale D (2015) Critical role of actin-associated proteins in smooth muscle contraction, cell proliferation, airway hyperresponsiveness and airway remodeling. Respir Res 16:134
Wang, Tao; Wang, Ruping; Cleary, Rachel A et al. (2015) Recruitment of ?-catenin to N-cadherin is necessary for smooth muscle contraction. J Biol Chem 290:8913-24
Jiang, Sixin; Tang, Dale D (2015) Plk1 regulates MEK1/2 and proliferation in airway smooth muscle cells. Respir Res 16:93
Liao, Guoning; Panettieri, Reynold A; Tang, Dale D (2015) MicroRNA-203 negatively regulates c-Abl, ERK1/2 phosphorylation, and proliferation in smooth muscle cells. Physiol Rep 3:
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

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