Dr Anthony Ashton

Research interests

Major Research Interests

Angiogenesis

Vascular injury and reactivity

Cell migration and differentiation

Role of small non-protein based mediators in the pathophysiology of disease

Narrative Report of Research

My principal area of interest in laboratory research lies in the investigation and application of angiogenic regulators in disease states, especially cancer and cardiac re-vascularization. In the past 11 years, I have studied the role of endothelial cell specific receptor isoforms on angiogenesis, examined the complicated relationships between inflammatory mediators on the outcome of angiogenesis and reperfusion injury and looked at the increasingly important role of cardiac specific modulators of apoptosis in the preservation of myocardium and mechanisms that might prevent myocyte apoptosis during reperfusion injury. As a part of these studies we have spanned the entire spectrum of techniques from recombinant protein production to cell culture models. More recently, we have used in vivo models to accurately model complex disease processes, such as angiogenesis, reperfusion injury, tumorigenesis and wound healing, and to take advantage of the power of mouse genetics in these investigations.

Our work on endothelial specific regulators of angiogenesis has focused on novel roles for the eicosanoid thromboxane (TX) A2. We found that TXA2 receptor stimulation alone is sufficient to inhibit angiogenesis through antagonism of connexin signaling, important for coordinating endothelial cell migration (an essential component of angiogenesis). Moreover, TXA2 receptor activation directly antagonizes the signaling of the angiogenic growth factors VEGF and FGF-2, both of which are undergoing clinical trials for pro-angiogenic therapy. These results may be vital to the reformulation of this therapy since many diseases recommended for pro-angiogenic therapy, such as re-vascularization of infarcted myocardium, also have locally or systemically elevated TXA2 levels. Further, only the B-isoform of the TXA2 receptor has this anti-angiogenic activity. Humans are the only species in which this receptor has been found and its function has previously been undetermined. Our work on this receptor establishes a novel role for isoform-specific regulation of angiogenesis by TXA2 receptors, provides the first pathophysiological significance of the two isoforms in humans, and clarifies the mechanism by these receptors regulate angiogenesis. This work has substantially altered the current model for the role of thromboxane A2 in vascular biology and has significant clinical implications for an emerging therapeutic regimen.

In ischemia-reperfusion injury, we recently described in detail a novel molecular interaction between the signaling pathways of the TXA2 and TNFa receptors that induces cardiac damage in part through limiting the angiogenic response from endothelial cells in the border area of an infarct. In an extension of these findings, we showed deletion of the TXA2 receptor decreases myocardial damage, compared to wild-type mice, in a murine model of cardiac infarction. This increased myocardial health directly correlated with lower rates of myocardial and endothelial cell apoptosis and increased survival. Thus,this phenomenon as one of potential clinical importance and may possibly explain the conflicting data on the role of TNFa in infarction.

Finally, we have recently been involved with characterizing the behavior of a very important cardiac-enriched protein, ARC (Apoptosis Repressor with CARD (Caspase Recruitment Domain)), that appears to function as the first master repressor of apoptosis. We have shown that ARC binds to and inhibits several proteins that regulate both the death receptor (extrinsic) and mitochondrial (intrinsic) pathways of apoptosis, including Fas, FADD, and Bax, and endows protection against cell death from stimuli which activate either pathway. Further, the final common pathway of apoptosis, after activation of Caspase 3, is also regulated by ARC. Specifically, ARC inhibits the proteolytic processing and activation of several Caspase-3 substrates responsible for dismantling the nucleus during the final phase of apoptosis. These are some of our most exciting results to date as no other protein has been demonstrated to inhibit nuclear degradation during apoptosis once Caspase 3 is activated.

Publications

2008 | 2007 | 2006 | 2005 | 2004 | 2003

Current national competitive grants*

2009

The role of oxygen sensing in regulation of trophoblast invasion
Morris J, Gallery E, Ashton A
NHMRC Project Grants ($388,350 over 3 years)

Connexin Isoform Switching Regulates Angiogenesis
Ashton A
NHMRC Project Grants ($449,500 over 3 years)

2008

Thromboxane receptor signalling in endothelial cells
Ashton A
NHMRC Project Grant ($553,750 over 3 years)

2006

Regulation Of Angiogenesis By Thromboxane Receptor Activation
Ashton A
NHMRC Career Development Awards ($436,250 over 5 years)

* Grants administered through the University of Sydney