Dr Robyn Midwinter
E:
T: +61 (2) 9036 3212
F: +61 (2) 9036 3038
Position
Post-Doctoral Fellow
Qualifications/Employment
PhD University of Otago New Zealand
Cellular signaling, HO-1 induction, endothelial biology, atherosclerosis, redox signaling
Research tools
Cellular biology and biochemistry
Research interests
It was recently shown that anti-oxidant protection against atherosclerotic disease was closely linked to the induction of heme oxygenase (HO-1). Induction of HO-1 has a number of protective activities in diseases associated with increased oxidative stress, such as cardiovascular, diabetes and inflammatory conditions. HO-1 is a stress inducible enzyme that catalyzes the degradation of heme. It best known biological function is that erythropoiesis, where the enzyme assists in the return of hemoglobin heme-derived iron to the bone marrow for use in heme biosynthesis.
My research interests are centred on cellular responses to stress, in particular how the induction of HO-1 leads to protection of the endothelium. My research efforts are focused on two main areas:
- How is HO-1 induced in endothelial cells?
We have previously shown that a class of compounds inhibit atherosclerosis in animals via induction of HO-1. HO-1 protects in several different ways, including the promotion of re-endothelialization, increasing the mobilization of endothelial progenitor cells, inhibition of smooth muscle cell proliferation, and altered cellular antioxidant activities. The mechanism underlying these protective effects are largely unknown. Understanding the novel signalling pathways involving HO-1 and how these lead to altered endothelial signalling is a major focus of my project. - How does induction of HO-1 in an injured vessel wall enhances re-endothelialization?
In response to vascular injury, the induction of HO-1 has been shown to accelerate the process of re-endothelialization. Such re-endothelialization involves both the migration of endothelial cells from undamaged vessels (J Exp Med 2006;203:1117) and circulating endothelial progenitor cells (manuscript submitted). I am currently investigating how HO-1 causes the increase in endothelial progenitor cells derived from the bone marrow.
Project: Signalling pathways induced by heme oxygenase-1 in endothelial cells
The induction of HO-1 has a number of protective activities in diseases associated with increased oxidative stress, such as cardiovascular, diabetes and inflammatory conditions. It was recently shown that anti-oxidant protection against atherosclerotic disease was closely linked to the induction of HO-1. There is mounting evidence that the up-regulation of HO-1 protects against vascular disease. In addition to promoting re-endothelialization, induction of HO-1 is though to protect via anti-inflammatory activities, inhibition of smooth muscle cell proliferation, and the promotion of endothelial growth. The signalling pathways involved in these protective mechanisms are not well understood. This project will investigate the signalling cascades induced by HO-1 induction and how they alter endothelial proliferation. It will also examine the role of the HO-1 derived compounds CO and Fe on downstream signalling events in endothelial cells. This project will use standard cell culture techniques, molecular biology, Western blotting along with biochemical assays.
- Wu BJ, Midwinter RG, Beck K, Wang Y, Changsiri D, Gamble J, Stocker R. Heme oxygenase-1 increases endothelial progenitor cells. Submitted to Arterioscler Thromb Vasc Biol. 2009 Oct;29(10):1537-42.
- Midwinter RG, Cheah FC, Moskovitz J, Vissers MC, Winterbourn CC. IB is a sensitive target for oxidation by cell-permeable chloramines: inhibition of NF-B activity by glycine chloramine through methionine oxidation. Biochem J 2006;396:71-78.
- Peskin AV, Midwinter RG, Harwood DT, Winterbourn CC. Chlorine transfer between glycine, taurine, and histamine: reaction rates and impact on cellular reactivity. Free Radic Biol Med 2005;38:397-405.
- Midwinter RG, Peskin AV, Vissers MC, Winterbourn CC. Extracellular oxidation by taurine chloramine activates ERK via the epidermal growth factor receptor. J Biol Chem 2004;279:32205-32211.
- Pullar JM, Thomson SJ, King MJ, Turnbull CI, Midwinter RG, Hampton MB. The chemopreventive agent phenethyl isothiocyanate sensitizes cells to Fas-mediated apoptosis. Carcinogenesis 2004;25:765-772.
