Immunopharmacology
Research Projects
Our Laboratory investigates the mechanisms and treatment of airway wall remodelling in asthma and other airway disorders. Airway smooth muscle growth and differentiation are central to this remodelling process. Cryptopharma funds studies on potential new anti-asthma and anti-inflammatory agents related to 2-methoxyestradiol (2-MEO) that inhibit tmesenchymal cell proliferation.
.....................................................
PhD Projects
The immunopharmacology laboratory has a number of potential PhD projects and the laboratory head, Professor Stewart would be pleased to discuss these in detail. Briefly, the main interest is in the remodelling of tissue during chronic inflammation an its potential for targeting by anti-inflammatory agents with actions complementary to those of glucocorticoids. We are particularly interested in understanding the influence of changes in the extracellular matrix on the efficacy of anti-inflammatory agents. Projects using animal models and those using human cell culture-based approaches are available. The laboratory has broad technical competence and applies state-of-the-art approaches to better understand tissue remodelling in airway, lung and other inflammatory diseases.
.....................................................
Airway Smooth Muscle
Airway smooth muscle can be stimulated to proliferate by a range of factors identified in the inflamed airways of asthmatics, including epidermal growth factor, basic fibroblast growth factor and thrombin. These growth factors increase levels of the key regulatory protein in the cell-cycle, cyclin D1, by increasing gene transcription and decreasing protein breakdown. Further definition of the pathways regulating cyclin D1 levels in airway smooth muscle may lead to identification of new pharmacological targets for regulation of excessive airway smooth muscle proliferation.
.....................................................
Anti-remodelling activity of currently used and potential anti-asthma agents
b2-adrenoceptor agonists including salbutamol inhibit DNA synthesis by arresting cell cycle progression late in G1 near the restriction point of the cell cycle, as do glucocorticoids. However, b2-agonists and other agents which increase cAMP reduce cyclin D1 protein levels by influencing its proteasome-dependent degradation, whereas glucocorticoids reduce levels by reducing mitogen-stimulated increases in cyclin D1 mRNA. Our recent work suggests that the extracellular matrix component collagen, induces resistance to some anti-remodelling actions of glucocorticoids.
.....................................................
Fibrosis
The extracellular matrix is expanded in fibrotic tissues. However, the ECM is not merely providing filler between cells, but also has a wide-ranging impact on cell function. Our studies are examining the impact of ECM components on the efficacy of anti-remodelling agents on fibrogenic activities of fibroblasts.
.....................................................
Steroid resistance
There is great interest in understanding the mechanisms that regulate sensitivity to anti-inflammatory glucocorticoids in chronic inflammatory conditions such as asthma. We have recently identified transforming growth factorb as a key mediator of steroid resistance. Current research is targetting the pathways that mediate this action of TGF-b to reveal strategies for the development of steroid-sensitising agents.
.....................................................
2-Methoxyestradiol
2-MEO is a metabolite of estradiol with low affinity for the estrogen receptor. 2-MEO is anti-angiogenic and reduces the proliferation of a number of different cell types by inhibiting the function of tubulin during formation of the mitotic spindle. 2-MEO arrests G1 progression that decreases entry of cells into S-phase of the cell cycle. Initial pre-clinical studies from other laboratories support the utility of this compound in regulating aspects of tumour growth. However, we have identified a lack of anti-tumour action in vivo in mouse models of human breast tumour, and 2-MEO has estrogenic activity that could accelerate tumour growth in some circumstances. Structure activity relationships amongst 2MEO analogues have the potential to provide new insights into the molecular targets of action of 2MEO.
.....................................................
Medicinal Chemistry
Collaborations between our group and the Research School of Chemistry at ANU have been developed. Our goal is to develop non-steroidal nuclear hormone receptor ligands having selectivity and efficacy as anti-remodelling agents.
.....................................................
Key References
* Bonacci JV, Schuliga M, Harris T, Stewart AG. (2006). Collagen impairs glucocorticoid actions in airway smooth muscle through integrin signalling. Br J Pharmacol;149(4):365-73.*Hughes RA, Harris T, Altmann E, McAllister D, Vlahos R, Robertson A, Cushman M, Wang Z and Stewart AG. 2-Methoxyestradiol and analogs as novel antiproliferative agents: Analysis of three-dimensional quantitative structure-activity relationships for DNA synthesis inhibition and estrogen receptor binding. Mol Pharmacol. 2002; 61:1053-69.
*Konopka TE, Barker JB, Bamford TL, Guida E, Anderson RL and Stewart AG. Nitric oxide synthase II gene disruption: implications for tumour growth and vascular endothelial growth factor production. Cancer Res. 2001;61:3182-3187.
*Hirst, S.J., Martin, J.G., Bonacci, JV., Chan, V., Fixman, E.D., hamid, Q., Herszberg, B., Lavoie, J-P., McVicker, C.G., Moir, L.M., Nguyen, T.T., Peng, Q., Ramos-Barbon, D., & Stewart, AG. (2004). Proliferative aspects of airway smooth muscle. Journal of Allergy and Clinical Immunology 114: S2-S17.
*Shepherd, M.C., Harris, T., Schuliga, M., Neylon, C.B. Brightling, C, Bradding, P. & Stewart, A.G. (2007). Intermediate conductance calcium-activated potassium channels are expressed in human airway smooth muscle cells and regulate proliferation. Am J Resp Cell Mol Biol 37(5):525-31.
* Stewart, AG., Bonacci, JV., Quan, L. (2004). Factors controlling airway smooth muscle proliferation in asthma. Current Allergy Reports 2004. 4:109-15.
* Sutherland, T.E., Schuliga, M., Harris, T., Eckhardt, B.L., Anderson, R.A., Quan, L., & Stewart, A.G. (2005). 2-methoxyestradiol is an estrogen receptor agonist that supports tumor growth in murine xenograft models of breast cancer. Clinical Cancer Research 11:1722-1732.
*Tara E. Sutherland, Robin L. Anderson, Richard A. Hughes, Emile Altmann, Michael Schuliga, James Ziogas & Alastair G. Stewart. 2-Methoxyestradiol - a unique blend of activities generates a new class of anti-tumour/anti-inflammatory agents. Drug Discovery Today, 12:577-584.
.....................................................