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.
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.
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