Airway smooth muscle cell proliferation plays an important role in the pathogenesis of airway smooth muscle layer thickening, cardinal features of asthma that affects nearly 250 million people worldwide. In addition, bronchial biopsy of patients with severe asthma suggests that airway smooth muscle migration contributes to smooth muscle thickening in the airways. The mechanisms that regulate smooth muscle cell proliferation and migration are not fully elucidated. Abi1 (Abl interactor 1) is an adapter protein that has a role in actin cytoskeletal remodeling in nonmuscle cells and smooth muscle contraction. Nevertheless, the role and mechanisms of Abi1 in smooth muscle cell proliferation and migration have not been previously investigated. Pilot studies have shown that Abi1 knockdown attenuates DNA synthesis and cell numbers enhanced by platelet-derived growth factor (PDGF), suggesting an important role of Abi1 in regulating airway smooth muscle cell proliferation.
In Aim 1, the role of Abi1 in regulating the Jak2 and STAT3 phosphorylation, and other pathways will be evaluated in cells upon stimulation with growth factors.
In Aim 2, the role of Abi1 in airway smooth muscle migration and its effectors will be evaluated.
In Aim 3, the role of Abi1 in allergen- induced airway smooth muscle thickening will be evaluated by using conditional Abi1 knockout mice. Moreover, the potential role of Abi1-associated pathways in human asthma will be determined. Completion of these studies should advance our knowledge regarding functional role and mechanism of the adapter protein Abi1 in smooth muscle cell proliferation and migration in vitro, and asthma pathogenesis in vivo. Obtaining this knowledge will facilitate the development of new therapy to treat asthma.

Public Health Relevance

Airway smooth muscle cell proliferation and migration play a critical role in the pathogenesis of asthma which affects nearly 25-30 million people in the United Sates and 250 million people worldwide. However, the cellular and molecular mechanisms that regulate smooth muscle cell proliferation and motility are not well elucidated. This research project is to unveil novel mechanisms that control airway smooth muscle growth and migration in vitro and the pathogenesis of asthma in vivo using advanced biotechnology. Obtaining this knowledge may disclose new biotargets for the development of new strategies to treat the disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL110951-06A1
Application #
9739806
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Lachowicz-Scroggins, Marrah Elizabeth
Project Start
2011-12-01
Project End
2023-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
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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