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.
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