In addition to myosin activation, the actin cytoskeleton undergoes reorganization in airway smooth muscle (a key regulator of airway tone) in response to contractile stimulation, which plays an essential role in the regulation of force development. The dynamic changes in the actin cytoskeleton may enable smooth muscle cells to adjust their structure and contractility in response to alterations in environments surrounding them. In contrast, the actin cytoskeleton of striated muscles is relatively stable. Myosin activation may serve as the """"""""engine"""""""" for smooth muscle contraction whereas remodeling of the actin cytoskeleton including actin polymerization may function as the """"""""transmission system"""""""" in smooth muscle. However, the cellular and molecular mechanisms that regulate the dynamic actin cytoskeleton are not well understood. Our pilot studies show that the actin-associated protein Abi is highly expressed in airway smooth muscle.
In Aim 1, physiological role of Abi in the regulation of actin polymerization in airway smooth muscle will be characterized.
In Aim 2, the physiological properties of the actin depolymerizer GMF in regulating actin depolymerization in airway smooth muscle will be evaluated.
In Aim 3, the formation and/or assembly of adherens junctions in airway smooth muscle upon contractile stimulation will be assessed. To accomplish the goal, several novel approaches such as a new technology to manipulate gene expression in smooth muscle tissues, cell-permeable peptides, the sensitive biochemical assay, and confocal fluorescent microscopy will be utilized. Completion of these studies should define the novel roles and regulation of the actin cytoskeleton and adherens junctions in airway smooth muscle, which may establish a new paradigm for the regulation of smooth muscle contraction. Obtaining this knowledge is fundamental to develop new strategies for more effective treatment of airway diseases such as asthma.
Asthma is characterized by airway hyperresponsiveness that largely stems from abnormal airway smooth muscle contraction. However, how smooth muscle contraction is regulated is incompletely elucidated. This project is to unveil previously unknown mechanisms that control airway smooth muscle contraction. Obtaining this knowledge is necessary for the development of new strategies to prevent/treat the disease.
|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|
|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|
|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|
|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|
|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|
|Wei, Saisai; Wang, Hongbo; Lu, Chunwan et al. (2014) The activating transcription factor 3 protein suppresses the oncogenic function of mutant p53 proteins. J Biol Chem 289:8947-59|
|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|
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