Projects

Manganese (Mn²⁺) is taken up in beta cells of islets via voltage-gated calcium channels. Since both Type 1 and Type 2 diabetes are characterised by diminished numbers and activity of beta cells, non-invasive detection of beta cells with manganese compounds may allow monitoring of treatment or disease progression. The contrast agent manganese gluconate is licensed in man and working with the Clinical Research Imaging Centre, we have demonstrated its utility in a rat model. In these studies, rats were administered 50% dextrose (2ml/kg) and enhancement of the liver was compared to enhancement in the pancreas following the administration of the contrast agent. Our subsequent studies will explore the utility in man in longitudinal studies.

Islet transplantation, where islets from donor pancreases are transplanted into the liver of patients with Type 1 diabetes, has the potential to cure Type 1 diabetes. However islets from up to 3 donor pancreases may be required for each patient because islets “engraft” or form blood vessels very poorly within the liver they are transplanted into. Working with Scottish National Blood Transfusion Service, who have manufactured human umbilical cord perivascular mesenchymal stromal cells (HUCPVC) to GMP grade, we have demonstrated that when the HUCPVCs are co-transplanted with islets into diabetic mice, they promote engraftment of islets, improving blood glucose control as compared with transplantation of islets alone. This means that potentially islets from one donor pancreas may be used in the future to cure diabetes, enabling more patients to be transplanted. Our aim is to understand further how HUCPVCs improve islet engraftment and take these cells into first-in-man clinical trials.

Despite the increased interest of preventing obesity, we know little about the origin(s) of adipose tissue. The majority of adipose tissue in our body is made up of white adipose tissue (WAT), which can be further divided into subcutaneous and visceral WAT. Our previous work, published in Nature Cell Biology, demonstrates that subcutaneous and visceral WAT differ in their developmental origins, and we identified mesothelium as one novel source of visceral adipose tissue. We are now building on this ground-breaking finding by further addressing the significance of adipose origin(s) and heterogeneity on adipose tissue development, homeostasis, and responses under diseased conditions.

Aortic stenosis is a condition whereby one of the heart valves (aortic valve) becomes narrowed, due to calcium deposition, over time. This can lead to chest pain, heart failure and sudden death. It is the commonest valve disease requiring surgery in the developed world and as the population becomes increasingly older, it is predicted that the prevalence of aortic stenosis will double in the next 20 years. Currently the only treatment is replacement of the aortic valve. Whilst this is excellent treatment, not everyone is suitable for it. The primary objective of our study is to determine whether 2 drugs used in the treatment of osteoporosis (a condition of bone thinning) can halt/retard the progression of aortic stenosis. 

clinicaltrials.gov NCT02132026

Myocardial fibrosis is a pathological feature contributing to the progression of a wide range of cardiovascular diseases. In this project, we validate cardiovascular magnetic resonance imaging tools to assess myocardial fibrosis in a mouse model of pressure overload.

This project aims to investigate the use of Positron Emission Tomography (PET) with ¹⁸F-Fluoro-Prolines for imaging and quantification of fibrosis.

Premature diseases and deaths associated with obesity are largely accounted for not by obesity itself, but by obesity-associated conditions including type 2 diabetes, atherosclerosis, fatty liver disease, polycystic ovary syndrome, and some cancers.   Understanding adipose remodelling, and how it goes awry in “metabolic” or “insulin resistance” syndrome (IRS), is critical to tackling “obesity-related” diseases. Study of rare human disorders featuring severe abnormalities of adipose distribution and caused by a single gene defect has great value.  It can reveal hypomorphic (partial loss-of-function) mutations in genes that would be lethal if fully “knocked out” or neomorphic (“change-of-function”) mutations that perturb or change normal gene function.

Glucocorticoid excess, particularly in adipose tissue, drives increased cardiovascular disease risk, including visceral obesity, hyperglycemia, dyslipidemia, and hypertension. Thus, efforts to reduce glucocorticoid action in adipose tissue as a treatment for cardiometabolic disease have both scientific and clinical merit. Our research is focused on the delivery mechanism through which glucocorticoids are ‘targeted’ to metabolic tissues, with the aims of not only advancing our understanding of glucocorticoid action in cardiometabolic disease, but identifying novel pathways to limit adverse glucocorticoid exposure.

Chronic kidney disease (CKD) is a risk factor for the development of end-stage kidney disease and cardiovascular disease. In CKD ongoing injury and attempts at self-repair occur simultaneously in the kidney, with disease progressing when the injury exceeds the ability of the kidney to repair. We are using a number of novel pre-clinical models and state-of-the-art technologies to identify pathways that may promote kidney injury or repair, so that we can develop therapies that favour regression of kidney disease.

25-30% of people have salt-sensitive blood pressure (BP), which is an independent risk factor for cardiovascular mortality. Mechanisms underpinning salt sensitive hypertension are not fully understood. However, our recent study (Evans et al, Circulation 2016) has suggested that abnormal glucocorticoid signalling can have a major contributory role in salt sensitivity. This project will systematically analyse hypothalamic-pituitary-adrenal axis function and glucocorticoid metabolism during the adaptation to high salt diets. We will use genetic engineering approaches to understand how high salt intake increases stress hormone production and how this leads to high blood pressure.

Obesity poses a major global healthcare challenge because it increases the risk of co-morbidities such as type 2 diabetes, fatty liver, heart disease and certain cancers. Our research focuses on mechanisms to harness adipocyte oxygen sensing to combat these obesity-related metabolic complications.

In the SCOT-HEART trial, we demonstrated the clinical effectiveness of computed tomography coronary angiography (CTCA) in patients attending the rapid access chest pain clinic with suspected angina pectoris due to coronary heart disease. This study demonstrated that CTCA increased diagnostic certainty, changed treatments and investigations, and halved the rate of future myocardial infarction. 

Randomised controlled trial of early surgery in asymptomatic patients with severe aortic stenosis and objective evidence of left ventricular decompensation (myocardial fibrosis on magnetic resonance imaging) clinicaltrials.gov NCT03094143

Manganese holds great promise for cardiac MRI. As a calcium analogue, manganese-enhanced MRI provides direct imaging of viable calcium handling, with potential to define myocardial viability more accurately than with current gold-standard methods, as well as detect calcium-handling dysfunction in failing cardiomyocytes.

There are around 915,000 survivors of myocardial infarction (MI, heart attack) currently living in the UK, many will have sustained damage to their heart that increases the likelihood of developing heart failure (HF) in the longer term. This project investigates the potential for drugs that inhibit intracellular regeneration of glucocorticoid to modify repair after heart attack by preventing infarct expansion and reducing the stimulus for the subsequent maladaptive remodeling that leads to HF.

The primary aim of our research is to characterise the molecular mechanisms through which resident cardiac endothelial cells contribute to vascular regeneration in the post-ischaemic heart.

5α-Reductases regulate metabolism of glucocorticoids and androgens. We have shown that inhibition of their activities either genetically or pharmacologically leads to increased risk of type 2 diabetes mellitus and are exploring the underlying mechanisms and degree of risk.

Considering the key role of long non-coding RNAs in gene expression, we aim to identify lncRNAs showing a change in expression during vasculature development or in pathology. The lncRNA regulation and potential mechanism of action is then investigated based on genome-wide data generated by our group or publicly available.

The High-STEACS research group are performing a series of stepped-wedge cluster randomised controlled trials (ClinicalTrials.gov Identifier: NCT01852123 and NCT03005158) to evaluate whether implementation of a high-sensitivity cardiac troponin I assay will reduce recurrent myocardial infarction and cardiovascular death in patients with suspected acute coronary syndrome across  tertiary and secondary care hospitals in Scotland.

Globally air pollution is believed to be responsible for several million premature deaths every single year. Many megacities see the continuous exposure of many millions of people to extremely high levels of air pollution, and represent a priority for interventions to reduce pollution, exposure or the associated health effects.

Air pollution is responsible for several million deaths worldwide per year, predominantly through cardiovascular mortality. The nanoparticles in traffic exhaust are especially harmful, although the biological mechanisms by which they induce detrimental cardiovascular effects remain to be fully established.

Too much salt in the diet can lead to an increase in morbidity, whether one is normotensive or hypertensive, but salt-sensitive hypertensives are particularly at risk. We used gene-editing technology to knockout the Hsd11b2 gene, which inactivates glucocorticoids, and have generated a model that faithfully represents the syndrome of apparent mineralocorticoid excess. 

Despite the accumulating experimental evidence, the complexity of miRNA-based phenotype remains yet to be fully understood. Thus, we set to identify miRNAs that are able to regulate endothelial cell function, by performing high-throughput phenotypic screening using a whole-genome miRNA library. Furthermore, bioinformatics and network analysis demonstrated that top hit miRNAs regulate common pathways in endothelial cells, such as BMP and TGF beta signalling pathway.

Retinal optical coherence tomography (OCT) has transformed how we image the eye, enabling non-invasive, high-resolution, cross-sectional imaging of the retina in vivo. There is growing interest in retinal OCT as a novel method for identifying patients at increased risk of cardiovascular disease.

The central hypothesis of VascmiR is that microRNAs (miRs) fundamentally control pathological remodelling of the vasculature. The complexity of vascular bed heterogeneity and subsequent response to injury, the potential importance of miRNA in vascular pathology and the paucity in knowledge relating to many facets of miRNA function in the vessel wall including target pathways, mechanistic features of miRNA-mediated cell:cell communication mediated by miRNA export and uptake etc.

Adenovirus Vector Technology: Next Generation Systems for Medical Therapy (AD-VEC)

AD-VEC involves two industrial and three academic partners with the aim to identify new adenoviral vectors as vehicles in novel medical applications for cardiovascular disease and infectious disease.

This will be achieved through broad knowledge exchange between partners with complimentary and cutting edge technological and indepth skills relating to adenovirus phylogeny, biology and pathology in order to explore and exploit adenovirus existing in nature as new vectors in areas of unmet clinical need such as cardiovascular disease and infectious disease.

Epidemiological studies have shown a link between exposure to an adverse environment in early life and an increased risk of cardiometabolic and neurodevelopmental disease. These ‘programmed’ effects are transmissible across generations through both male and female lines (Drake et al).

Steroid hormones circulate in blood and penetrate tissues where they have their actions. The amounts of steroids in tissue subregions can be modulated by local enzymes and transporters, making it vital to understand regional steroid amounts e.g. in inflamed sites, in tumours or in brain regions. Mass spectrometry imaging is a powerful technique used to localise molecules in tissue sections, providing molecular distribution.

Advanced in vivo imaging is key to cardiac phenotyping as well as for identification of myocardial injury and characterisation of structure, function and  molecular processes during remodelling of the heart in disease.

There has been an exponential increase in the production of manufactured nanomaterials (MNMs) for a wide variety of applications, including engineering, electronic circuitry, food preservatives, clothes, water purification, batteries, paints, sun-creams and medical therapeutics. However, research into the potential for MNM exposure to induce toxicity is lagging behind the interest in their development.

The pandemic of obesity threatens to reverse the downward secular trends in cardiovascular disease because of its associations with hyperglycaemia, dyslipidaemia and hypertension (the Metabolic Syndrome). Research in Edinburgh has focused on steroid hormones as mediators of the metabolic complications of obesity and the progression to cardiovascular disease (Ann Int Med 2004, PNAS 2005).