Visit Dr. Toews Laboratory
MYRON L. TOEWS
Durham Research Center, Room 3012
985800 Nebraska Medical Center
Omaha, NE 68198-5800
Keywords: receptors and cell signaling; adrenergic receptor drugs and actions; lipid mediators of lung disease; agricultural lung disease; EGF receptor signaling and regulation in airway diseases
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Dr. Toews discusses a career in pharmacology and his research in hog barn dust and lung disease.
Current studies in my laboratory are focused on extracellular mediators and their receptors and signaling pathways in relation to lung diseases other than lung cancer, mainly diseases of the "airways" such as asthma, pulmonary fibrosis and chronic bronchitis.
One focus is on the roles of the simple lipid mediator lysophosphatidic acid (LPA) in airway disease. LPA is known to be released at sites of tissue injury and to mediate wound repair, for example when we cut our finger. Many diseases of the lung, including asthma, chronic bronchitis and pulmonary fibrosis, are thought to result from repeated lung injury followed by inappropriate repair responses that lead to an altered structure of the lung tissue. We published many studies showing disease-relevant effects of LPA on lung cells. Recent studies from other groups have now confirmed the importance of LPA in airway disease using knockout mice. We continue to work on this project, with a major focus on the sources of this LPA and on identifying the specific LPA receptors and signaling pathways involved in these airway diseases. The long-term goal is to identify drugs that alter the production, destruction or actions of LPA to treat these lung diseases.
Another focus is on the cellular and molecular mechanisms involved in development of obstructive lung disease in agricultural workers exposed to animal barn dusts, especially hogbarn dust. Our recent studies have shown that an extract of this hogbarn dust both activates and then down-regulates receptors for epidermal growth factor (EGF) receptors on airway epithelial cells. LPA shares these effects with the hogbarn dust, and our prior studies of LPA regulation of EGF receptors are guiding our studies of the hogbarn dust effects. We are also working to identify the specific factors in the dust that mediate the disease-relevant effects on airway epithelial cells, which may allow us to develop new and more specific therapies
Adrenergic receptor signaling and regulation have been long-term interests in my laboratory, and another current focus is on signaling pathways by which these receptors regulate cell growth. Patients with asthma have excess airway smooth muscle cell growth, which makes their disease worse. Beta-2 adrenergic receptor agonists, which are used to "open up" asthmatic airways, can also reduce airway smooth muscle cell growth. Our recent studies show that these effects are mediated through cyclic AMP activation of the protein EPAC (Exchange Protein Activated by CyclicAMP) rather than through the more traditional cyclic AMP target protein kinase A. We are further characterizing this novel growth-inhibiting pathway as a target for new asthma therapies.
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- To dissect the detailed molecular mechanisms involved in receptor activation and inactivation, especially for LPA receptors, EGF receptors, and adrenergic receptors
- To use this information to develop more selective, more effective, and safer drugs, especially for airway disease
Additional publications in PubMed
- Dodmane PR, Schulte NA, Heires AJ, Band H, Romberger DJ, and Toews ML. Airway epithelial EGF receptor mediates hogbarn dust-induced cytokine release but not Ca2+ response. Am. J. Respir. Cell Mol. Biol. 201145:882-888
- Jiang H, Abel, PW, Toews ML, Deng ., Casale TB, Xie Y, and Tu Y. Phosphoinositide 3-kinase γ regulates airway smooth muscle contraction by modulating calcium oscillations. J. Pharmacol. Exptl. Ther. 334:703-709, 2010
- Tian C, Shao CH, Fenster DS, Mixan M, Romberger DJ, Toews ML, Bidasee KR. Chloroform extract of hog barn dust modulates skeletal muscle ryanodine receptor calcium-release channel (RyR1). J Appl Physiol. 2010 Sep;109(3):830-9
- Kassel, K.M., N.A. Schulte, and M.L. Toews. Modulation of epidermal growth factor receptor binding to human airway smooth muscle cells by glucocorticoids and beta-2 adrenergic receptor agonists. Am. J. Physiol.-Lung Cell Mol. Physiol., (2009) 296(4):L693-9
- Hashimoto M., X. Wang, L. Mao, T. Kobayashi, S. Kawasaki, N. Mori, M.L. Toews, H.J. Kim, D.R. Cerutis, X. Liu and S.I. Rennard SI. Sphingosine 1-phosphate potentiates human lung fibroblast chemotaxis through the S1P2 receptor. Am. J. Respir. Cell Mol. Biol. 39:356-363, 2008
- Bruchas, M.R., M.L. Toews, C.S. Bockman and P.W. Abel. Characterization of the α1-adrenergic receptor subtype activating extracellular signal-regulated kinase in submandibular gland acinar cells. Eur. J Pharmacol. 578:349-358, 2008
- Kassel, K.M., T.A. Wyatt, R.A. Panettieri, Jr. and M.L. Toews. Inhibition of human airway smooth muscle cell proliferation by β2 adrenergic receptor activation and cAMP-elevating agents: Evidence for EPAC involvement. Am. J. Physiol: Lung Cell Mol. Physiol. 294:L131-138, 2008
- Kassel, K.M., P.R. Dodmane, N.A. Schulte and M.L. Toews. Lysophosphatidic acid induces rapid and sustained decreases in epidermal growth factor binding via different signaling pathways in BEAS-2B airway epithelial cells. J. Pharmacol. Exptl. Ther. 325:809-817, 2008
- Kassel, K.M., N.A. Schulte, S.M. Parker, A.D. Lanik and M.L. Toews. Lysophosphatidic acid decreases epidermal growth factor receptor binding in airway epithelial cells. J. Pharmacol. Exptl. Ther. 323:109-118, 2007
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Dr. Toews biographical information