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Research Interests:

A/Profs Thomas' co-leads the Cardiovascular and Metabolic Disease research group at UNSW with Prof. Kerry-Anne Rye. His research focusses onÌýunderstanding the oxidative and inflammatory processes promoting endothelial dysfunction and cardiovascular disease and the development of new therapeutics targeting these processes. He also has a long-term interest in the biochemical regulation and patho-physiological roles of the central immune regulatory heme enzyme called indoleamine 2,3-dioxygenase (IDO1).ÌýÌý

1. Development of novel antioxidant and anti-inflammatory therapeutics for treating cardiovascular disease.

We are developing new anti-inflammatory therapies that prevent the development of atherosclerotic lesions, which can rupture and stop blood from getting to the heart, causing a heart attack. We are also asking whether these anti-inflammatory therapies can heal the tissue damage that is caused by a heart attack. In particular, we are complexing a new class of immune modulatory nanoparticles with clinically viable anti-inflammatory peptides or small molecule drugs targeting specific oxidative and pro-inflammatory enzymes to suppress inflammation in the heart and blood vessels. We envisage that these new nanotherapeutics will reduce the risk of having a heart attack and improve recovery after a heart attack. This research involves biochemistry, molecular biology, pharmacology, vascular biology, and pre-clinical models of cardiovascular disease.

2. Identification of the redox reactions and cell signaling pathways controlling endothelial function and phenotype

The endothelium is critical for the maintenance of vascular homeostasis. Cardiovascular disease patients are characterized by the formation of a dysfunctional endothelium that increases their risk of experiencing a clinical cardiovascular events such as a heart attack.ÌýConsiderable evidence shows that endothelial dysfunction is due to oxidative stress in the blood vessel wall and there is great interest in defining the oxidative processes and cell signaling events involved. A recently discovered form of endothelial dysfunction promoting the formation of vulnerable atherosclerotic lesions is the process of endothelial-to-mesenchymal transition (EndMT), which refers to the genetic reprogramming of homeostatic endothelial cells into pro-inflammatory mesenchymal-like cells. Current interest surrounds understanding the stimuli and biochemical signaling pathways underlying EndMT. We are currently studying roles for mitochondria and associated redox reactions in driving EndMT. This research has the potential to discover new molecular targets for suppressing EndMT that can lead to the development of new therapeutics for treating endothelial dysfunction and cardiovascular disease.Ìý Ìý

3. Roles and Regulation of the critical immune regulatory enzyme IDO1

Indoleamine 2, 3-dioxygenase1 (IDO1) is an intracellular heme enzyme that catalyzes the catabolism of L-tryptophan (L-Trp) along the kynurenine pathway. IDO1 represents a central immune regulatory enzyme . Thus, expression of IDO1 in professional antigen presenting cells or tumor cells and resultant depletion of L-Trp, the least abundant essential amino acid, inhibits T cell activation to promote immune suppression and tolerance during inflammation, transplantation, auto-immunity, infectious disease and cancer.Ìý In light of the important immune regulatory roles of IDO it is important to understand how the enzyme is controlled. Our previous studies were the first to describe post-translational regulation of IDO and this project aims to characterize the post-translational modifications involved and the extent to which they govern the immune regulatory actions of antigen presenting cells and tumour cells. Identification of how IDO1 is regulated may facilitate the development of novel drug strategies to modulate IDO activity in vivo.