Training

Investigation of the role of adenosine deaminase 2 in monocyte and endothelial homeostasis and in the pathogenesis of vascular injury

Funder: Wellcome Trust

Researcher: Dr Andrew Porter

Supervisors: Professor Justin Mason, Dr Adam Byrne, Dr Taryn Youngstein

Understanding of disease pathogenesis and mechanisms of vascular injury in the vasculitides remains limited, while morbidity and treatment toxicity remains high. In 2014, a monogenic vasculitis was described (DADA2) in which there is a deficiency of the enzyme Adenosine Deaminase 2 (ADA2). This is associated with a syndrome of vascular inflammation affecting small-medium arteries and complicated by digital gangrene and stroke. This phenotype suggests ADA2 is critical for the maintenance of vascular integrity and resistance to endothelial dysfunction, and therefore of relevance to diseases in which vascular injury is implicated. However, the mechanisms through which ADA2 binds to the vascular endothelium and exerts its effects remain unknown. This project will determine the importance of ADA2 by investigating the hypothesis that: (i) ADA2 is critical for monocyte homeostasis and maintenance of the endothelial barrier, and (ii) ADA2 deficiency results in monocyte activation, cytokine synthesis and enhanced adhesion resulting in loss of vascular endothelial integrity. A variety of cell and molecular biology techniques will be applied, including study of patient-derived endothelial cells and monocytes and the functional mechanistic analysis of monocyte:endothelial cell interactions. In Aim 3, the vasculoprotective impact of therapeutic intervention against the deleterious actions of ADA2-deficient monocytes will be determined.

Biomarker analysis in large vessel vasculitis

Researcher: Dr Martha Peverelli

Supervisor:

Investigating the relationship between inflammation and the pro-coagulant pathway in ANCA-associated vasculitis

Researcher: Dr Aruni Ratnayake

Supervisors: Professor Frederick Tam and Dr Tom McKinnon

ANCA-associated vasculitis (AAV) causes glomerulonephritis (GN), which in severe cases results in rapidly progressive kidney injury and life threatening lung haemorrhage. AAV is also associated with increased incidence of systemic arterial and venous thrombosis, raising the risk of ischaemic heart disease, stroke and pulmonary emboli. The mechanisms linking inflammatory processes of AAV and the clotting cascade are poorly understood. I hypothesise that inflammatory processes of AAV activate the procoagulant cascade causing glomerular and systemic thrombosis, with a possible positive feedback loop linking the two processes. Anticoagulation may therefore attenuate renal disease and associated accelerated cardiovascular disease; however there is a caveat, as some of these patients are prone to lung haemorrhage. I shall use multiple experimental approaches to further investigate these interactions, including in vitro study of ANCA or cytokine activated monocytes or neutrophils with endothelial cells under sheer stress, analysis of patients’ samples and intervention studies in vivo. The hope is my work will elucidate characteristics in patients with AAV that increase the rate of thrombus formation and its relationship to inflammation. This will allow clinicians to balance a patient's risk of thrombus formation or lung haemorrhage. If there is crosstalk between the two processes, then anticoagulant medications could be targets for novel therapeutic agents for AAV, reducing inflammation and subsequent end-organ damage.