Durham Research Center, 3042
985800 Nebraska Medical Center
Omaha, NE 68198-5800
Keywords: Receptors and cell signaling; Agricultural lung disease; EGF receptor signaling and regulation in airway diseases; Lipid mediators of lung disease; Adrenergic receptor drugs and actions
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Dr. Toews discusses a career in pharmacology and his research in hog barn dust and lung disease.
Research in my laboratory has always been focused on the "receptors" with which drugs interact and on the "signaling pathways" by which these receptors regulate cell function in response to those drugs. Better understanding of both the receptors and their signaling pathway components may reveal new targets for improved drug therapy or even prevention. A particular focus has been on how these receptors and signaling pathways change with chronic activation or inhibition by drugs or in disease states.
One major focus our studies is the diverse group of extracellular mediators and their receptors and signaling pathways that are involved in diseases of the "airways", such as asthma, pulmonary fibrosis, and chronic bronchitis. The current focus is on the cellular and molecular mechanisms involved in development of obstructive lung disease in agricultural workers exposed to animal barn dusts, especially the dust from large hog-feeding operations, which are of particular relevance to Nebraska and Iowa. Our recent studies have shown that an extract of this dust both activates and then down-regulates receptors for epidermal growth factor (EGF receptors) on airway epithelial cells. We are also working to identify the specific factors in the dust that mediate the disease-relevant effects on airway epithelial cells. Proteomics analysis of all of the proteins in the dust extract identified heat-stable proteases, and subsequent studies have shown that these proteases seem to mediate the hog barn dust responses that are not mediated by EGF receptors. Drugs targeting both EGF receptors and proteases are already available, which may allow us to develop new therapies for preventing or treating the occupational and environmental diseases caused by the dust. Another completely novel signaling molecule has been identified in recent studies and is the focus of intense current investigation.
The second project currently ongoing in the laboratory is a new collaboration with Dr. Jeff French at the University of Nebraska – Omaha to study the role of the neuropeptide oxytocin and its receptors in social behavior. Humans and most other primates express oxytocin with the amino acid leucine at position 8. However, an oxytocin variant with proline instead of leucine at position 8 is present in many New World Monkeys, and the presence of proline versus leucine oxytocin appears to strongly modulate the social interaction patterns of each species, including monogamy versus polygamy and shared parenting. Work in our laboratory is focused on characterizing the interactions of both forms of oxytocin with the receptors expressed by each of the different behavioral groups. Because of evidence that oxytocin also regulates certain aspects of human social interactions also, notably autism spectrum disorders, these studies hold strong promise to provide directions for novel interventions to modulate human behavioral disorders.
Finally, because my laboratory remains one of the most experienced in classic methods of studying receptors and cell signaling, I have authored many articles on proper methods and analyses for these experiments, including two recent articles for a focused journal issue on problems with reproducibility in studies of drug action that are thought be slowing progress on new drug development.
- To identify active components in hogbarn dust and their receptors and signaling pathways, with the hope of preventing or alleviating lung diseases associated with working in these facilities
- To establish whether differential interaction with cell surface receptors is the basis for the different behavioral responses to leucine versus proline variants of oxytocin
- To leverage a better molecular understanding of receptors and their signaling pathways for development of new drugs with improved safety and effectiveness for diverse diseases
Nordgren TM, Heires AJ, Bailey KL, Katafiasz DM, Toews ML, Wichman CS, Romberger DJ. Docosahexaenoic acid enhances amphiregulin-mediated bronchial epithelial cell repair processes following organic dust exposure. Am J Physiol Lung Cell Mol Physiol. 2017 Nov 2:ajplung002732017. PMID: 29097425.
Ng TM, Toews ML. Impaired norepinephrine regulation of monocyte inflammatory cytokine balance in heart failure. World J Cardiol. 2016 Oct 26;8(10):584-589. PMID: 27847559. PMCID: PMC5088364
Xie Y, Jiang H, Zhang Q, Mehrotra S, Abel PW, Toews ML, Wolff DW, Rennard S, Panettieri RA, Jr., Casale TB, Tu Y. Upregulation of RGS2: a new mechanism for pirfenidone amelioration of pulmonary fibrosis. Respir Res. 2016, 17:103. PMID: 27549302. PMC4994235.
Jiang H, Xie Y, Abel PW, Wolff DW, Toews ML, Panettieri RA, Jr., Casale TB, Tu Y. Regulator of G-protein signaling 2 repression exacerbates airway hyper-responsiveness and remodeling in asthma. Am J Respir Cell Mol Biol. 2015, 53:42-9. PMID: 25368964. PMC4566111.
Li YJ, Kanaji N, Wang XQ, Sato T, Nakanishi M, Kim M, Michalski J, Nelson AJ, Farid M, Basma H, Patil A, Toews ML, Liu X, Rennard SI. Prostaglandin E2 switches from a stimulator to an inhibitor of cell migration after epithelial-to-mesenchymal transition. Prostaglandins Other Lipid Mediat. 2015, 116-117:1-9. PMID: 25460827.
Romberger DJ, Heires AJ, Nordgren TM, Souder CP, West W, Liu XD, Poole JA, Toews ML, Wyatt TA. Proteases in agricultural dust induce lung inflammation through PAR-1 and PAR-2 activation. Am J Physiol Lung Cell Mol Physiol. 2015, 309:L388-99. PMID: 26092994. PMC4538230.
Bylund DB, Toews ML. Quantitative versus qualitative data: the numerical dimensions of drug action. Biochem Pharmacol. 2014, 87:25-39. PMID: 23933389.
Kenakin T, Bylund DB, Toews ML, Mullane K, Winquist RJ, Williams M. Replicated, replicable and relevant-target engagement and pharmacological experimentation in the 21st century. Biochemical pharmacology 2014, 87:64-77. PMID: 24269285.
Tian C, Moore CJ, Dodmane P, Shao CH, Romberger DJ, Toews ML, Bidasee KR. Dust from hog confinement facilities impairs Ca2+ mobilization from sarco(endo)plasmic reticulum by inhibiting ryanodine receptors. J Appl Physiol (1985). 2013, 114:665-74. PMID: 23288552. PMC3615592.
Michalski J, Kanaji N, Liu X, Nogel S, Wang X, Basma H, Nakanishi M, Sato T, Gunji Y, Fahrid M, Nelson A, Muller KC, Holz O, Magnussen H, Rabe KF, Toews ML, Rennard SI. Attenuation of inhibitory prostaglandin E2 signaling in human lung fibroblasts is mediated by phosphodiesterase 4. Am J Respir Cell Mol Biol. 2012, 47:729-37. PMID: 23043089. PMC5459525.
Bylund DB, Toews ML. Radioligand binding methods for membrane preparations and intact cells. Methods Mol Biol. 2011, 746:135-64. PMID: 21607856.
Dodmane PR, Schulte NA, Heires AJ, Band H, Romberger DJ, Toews ML. Airway epithelial epidermal growth factor receptor mediates hogbarn dust-induced cytokine release but not Ca2+ response. Am J Respir Cell Mol Biol. 2011, 45:882-8. PMID: 21441380. PMC3208609.
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. Sep;109(3):830-9, 2010. PMID: 20576841.
Kassel KM, Wyatt TA, Panettieri, Jr RA, Toews ML: 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. PMID: 17993585.
Kassel KM, Dodmane PR, Schulte NA, Toews ML: 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. PMID: 18309089.Additional publications in PubMed.