CoRE Supported Research Projects

CoRE Supported Research Projects

The current BHF Centre of Research Excellence actively encourages and facilitates interdisciplinary collaborations in cardiovascular science that encompass expertise from the physical science. This provides continuity from investments during the initial REA funding which supported dedicated PhD studentships for graduates of the physical sciences and key investments in chemistry, physics and bioinformatics.  The REA supports research in four key themes: Metabolic Risk Factors, Renal and Vascular Risk Factors, Vascular Injury, Inflammation and Repair, and Stem Cells and examples of collaborative interdisciplinary research include support for the Clinical Research Imaging Centre (including PET chemistry), the establishment of bespoke SPIM microscopy facilities and novel software, together with Professor John Girkin (Durham) and Dr Jonny Taylor (Glasgow); the establishment and use of a zebrafish facility for the development of novel chemical catalysts, pioneering cell ablation and cardiovascular development with Professors Mark Bradley (Edinburgh), John Girkin (Durham) and Calum MacRea (Harvard); CARS microscopy for imaging steroids in vivo (Professor Alisdair Elflick, Edinburgh); 3D printing applications for cardiovascular research with Professor John Haycock (Bioengineering, Sheffield) and Richard Collins (Edinburgh); and bioinformatics with Professor Tom Freeman (The Roslin Institute).

Metabolic Risk Factors:

Utilisation of Novel Contrast Agents in Studies of Type 1 and Type 2 Diabetes

Studying origins and heterogeneity of adipose tissue: a novel way of understanding aetiology of obesity

Exploiting the population isolate jackpot effect

Improving cardiometabolic health by controlling glucocorticoid delivery to adipose tissue

Adipocyte Oxygen Sensing Machinery: A regulator of metabolic disease and beyond

Ion mobility Mass Spectrometry to enhance specificity of Metabolomic profiling with Mass Spectrometry Imaging

5α-Reductases and risk of metabolic disease

Brown adipose tissue as a novel therapeutic target for obesity and type 2 diabetes

A classification system for zebrafish adipose tissues

Does obesity lead to effects on the epigenome?

Bone marrow adipose tissue: a novel regulator of cardiometabolic health?

Steroid metabolism

Genetic Identification of an adipocyte-expressed anti-diabetic target in mice selected for leanness

Renal and Vascular Risk Factors

The effects of endogenous and exogenous glucocorticoids on placental vascular development and hemodynamic function

Identifying pathways of injury and resolution in the kidney

The relationship between salt and glucocorticoids: implications for salt-sensitive hypertension

Using Mass Spectrometry Imaging to resolve corticosteroid action in the aldosterone-sensitive distal nephron

Development of an in vitro model of kidney collecting duct using mCCDcl1 cells

A model of salt-sensitive hypertension

Bioinformatics approaches to understand mechanisms of disease of cardiovascular disease

Retinal optical coherence tomography (OCT): using the eye as a window on the kidney

Connecting salt appetite to cardiovascular and kidney disease

Discovering genetic modifiers of early kidney disease

Vascular Injury, Inflammation and Repair

Cardiac 23Na MRI

Adverse cardiac remodelling under pressure overload

Novel Imaging Biomarker for Detection of Regional Cardiovascular Inflammation using PET

PET imaging biomarkers of fibrosis

The role of inflammation in zebrafish heart injury and repair

The Scottish COmputed Tomography of the HEART (SCOT-HEART) Trial

Prediction of Recurrent Events with 18F-Fluoride to Identify Ruptured and High-risk Coronary Artery Plaques in Patients with Myocardial Infarction

Clinical Translation: Manganese-Enhanced MRI of the Myocardium

Reactivating ancestral heart regeneration programs in mammals

11ßHSD1 inhibition: a distinctive acute-myocardial infarction intervention for promotion of peri-infarct vascularization, reduction of infarct expansion and prevention of heart failure

Epigenetics regulation of endothelial cells in vascular disease

Extracellular vesicle-mediated delivery of long non-coding RNA: Implications for vascular repair and regeneration

Computational approaches to study lncRNAs in vascular biology and disease

High-sensitivity cardiac troponin in the evaluation of suspected acute coronary syndrome

High-Sensitivity Cardiac Troponin and Coronary Heart Disease

Phenotypic analysis of miRNAs to promote vessels growth

Glucocorticoid receptor in the early life programming of cardiac resilience

Stem Cells

Taking GMP Grade Perivascular Mesenchymal Stromal Cells to First-in-Man Clinical Trials

Assessing the maturation, specification and function of vascular endothelial cells derived from human embryonic stem cells

Understanding mechanisms of regeneration by resident endothelial cells in the post-ischaemic heart

Selected Outputs

  • Chau Y-Y, Bandiera R, Serrels A, Martinez Estrada O, Qing W, Lee M, Slight J, ThornburnA, Berry R, McHaffie S, Stimson RH, Walker BR, Munoz Chapuli R, Schedl A, Hastie N. Nature Cell Biology, 2014 Visceral and subcutaneous fat have different origins and evidence supports amesothelial source. Apr; 16(4): 367–375. doi:  10.1038/ncb2922 PubMed PMID: PMID: 24609269, PubMed Central: PMCID: PMC4060514.

The REA provided the essential resources facilitating collection of human adipose tissue that was used in the study (lean v.s. obese and visceral v.s. subcutaneous), confirming the finding in human and strenthening its translational importance. The first author was subsequently appointed as an EPICT fellow through the REA2 and is now in the Edinburgh Scientific Academic Track scheme linking her to an open-ended contract in the Centre for Cardiovascular Science.

 

  • Evans LC, Ivy JR, Wyrwoll C, McNairn JA, Menzies RI, Christensen TH, Al‐Dujaili EAS, Kenyon CJ, Mullins JJ, Seckl JR, Holmes MC, Bailey MA. Conditional deletion of Hsd11b2 in the brain causes salt appetite and hypertension. Circulation 2016 Apr 5; 133(14): 1360–1370. doi:  10.1161/CIRCULATIONAHA.115.019341. PubMed PMID: 26951843, PubMed Central PMCID: PMC4819772

Early development of this work was critically dependent on REA funding into PhD studentships for RM and JMcN. Both were cross disciplinary. RM is from Physics and he contributed underpinning analysis of BP telemetry that fed this and other studies. REA also contributed by investment into the in vivo physiology programme and by pump-priming the radio-telemetry study that was a central part of this project. 

 

  • Morton NM, Beltram J, Carter RE, Michailidou Z, Gorjanc G, McFadden C, Barrios‐Llerena M, Rodriguez‐Cuenca S, Gibbins M, Aird RE, Moreno‐Navarrete JM, Munger SC, Svenson KL, Gastaldello A, Ramage L, Naredo G, Zeyda M, Wang ZV, Howie AF, Saari A, Sipila P, Stulnig T, Gudnasson V, Kenyon CJ, Seckl JR, Walker BR, Webster SP, Dunbar DR, Churchill GA, Vidal‐Puig A, Fernandez‐ Real JM, Emilsson V, Horvat S. Genetic identification of thiosulfate sulfur‐transferase as an adipocyte‐expressed anti‐diabetic target in mice selected for leanness. Nature Medicine 2016, Jul; 22(7): 771–779. doi:  10.1038/nm.4115. PubMed PMID: 27270587, PubMed Central PMCID: PMC5524189

This output was primed and facilitated by the REA through provision of essential bioinformatics for the analysis of the complex datasets that led to the initial discovery of the adipose tissue-specific lean gene, leading to the wet laboratory work.

 

  • Nixon M, Mackenzie SD, Taylor AI, Homer NZM, Livingstone DE, Mouras R, Morgan RA, Mole DJ, Stimson RH, Reynolds RM, Elfick APD, Andrew R, Walker BR. ABCC1 confers tissue‐specific sensitivity to cortisol versus corticosterone; a rationale for safer glucocorticoid replacement therapy. Science Translational Medicine, 2016 Aug 17;8(352):352ra109.  PubMed PMID:27535620

This output deployed CARS microscopy to localise and quantify intracellular steroid levels, essential to the central message from this research. This was developed in a collaboration with Prof Alistair Elfick in Engineering at the University of Edinburgh and was funded by a pump priming award from REA.

 

  • Clavadetscher J, Hoffman S, Lilienkampf A, Mackay L, Yusop RM, Rider SA, Mullins JJ, Bradley M. Copper catalysis in living systems and in situ drug synthesis. Angewandte Chemie (International ed.) 2016 Dec 12;55(50):15662-15666. doi: 10.1002/anie.201609837. PubMed PMID: 27860120. 

REA2 support (including salary support for Dr Seb Rider) was critical for the demonstration, in vivo, of the efficacy of copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction, a pivotal advance in chemical ligation strategies. The initial REA-funded Zebrafish facility leveraged major equipment funds from the Wellcome Trust which enabled its expansion allowing multiple interdisciplinary collaborations such as this one to be undertaken.

 

  • Newby D, Forsythe R, McBride O, Robson J, Vesey A, Chalmers R, Burns P, Garden OJ, Semple S, Dweck M, Gray C, MacGillivray T, Wang C, Koutraki YG, Mitchard N, Cooper A, van Beek E, McKillop G, Ho W, Fraser L, Cuthbert H, Hoskins P, Doyle B, Conlisk N, Stuart W, Berry C, Roditi G, Murdoch L, Holdsworth R, Scott E, Milne L, Strachan F, Wee F, Oatey K, Graham C, Murray G, Milne G, Bucukoglu M, Goodman K, Kaczynski J, Shah A, Tambyraja A, Brittenden J, Houston G, Lambie R, Norrie J. Aortic wall inflammation predicts abdominal aortic aneurysm expansion, rupture, and need for surgical repair. MA3RS Study Investigators. Circulation. 2017 Aug 29;136(9):787-797. doi: 10.1161/CIRCULATIONAHA.117.028433. PubMed PMID: 28720724, PubMed Central PMCID: PMC5571881.

The REA has supported the development of magnetic resonance contrast-enhanced imaging through the provision of equipment (coils) and medical physics support (Scott Semple). This programme of work was developed from an initial BHF-funded fellowship (FS/07/060) performed on the BHF 3T magnetic resonance scanner. This has required a lot of early development work supported by the REA awards and involved an interdisciplinary collaboration between Cardiology, Radiology, and Vascular Surgery.

 

  • Forsythe RO, Dweck MR, McBride OMB, Vesey AT, Semple SI, Shah ASV, Adamson PD, Wallace WA, Kaczynski J, Ho W, van Beek EJR, Gray CD, Fletcher A, Lucatelli C, Marin A, Burns P, Tambyraja A, Chalmers RTA, Weir G, Mitchard N, Tavares A, Robson JMJ, Newby DE. 18F-Sodium fluoride uptake in abdominal aortic aneurysms: The SoFIA3 Study. Journal of the American College of Cardiology. 2018 Feb 6;71(5):513-523. doi: 10.1016/j.jacc.2017.11.053. PubMed PMID: 29406857, PubMed Central PMCID: PMC5800891.

The REA2 helped support Dr Adriana Tavares (salary and consumables) to deliver the micro-PET/CT work from tissue obtained from abdominal anortic aneurysms. This played a crucial role in validating the 18F-fluoride approach. This involved an interdisciplinary collaboration between Cardiology, Radiology, Vascular Surgery and Pathology.  This study was ultimately funded by the Chief Scientist Office in Scotland.

 

  • Weir G, Ramage LE, Akyol M, Rhodes JK, Kyle CJ, Fletcher AM, Craven TH, Wakelin SJ, Drake AJ, Gregoriades ML, Ashton C, Weir N, van Beek EJR, Karpe F, Walker BR, Stimson RH. Substantial metabolic activity of human brown adipose tissue during warm conditions and cold-induced lipolysis of local triglycerides. Cell Metabolism. 2018 Jun 5;27(6):1348-1355. doi:  10.1016/j.cmet.2018.04.020. PubMed PMID: 29805098, PubMed Central PMCID: PMC5988566.

The REA2 helped by funding development of imaging probes utilised for 18FDG PET/CT imaging to guide insertion of catheters directly into human brown adipose tissue. This research also involved new interdisciplinary collaborations between the Interventional Radiology, Medical Physics and CVS to develop microdialysis as a novel in vivo tool tool to measure substrate utilisation by human brown adipose tissue.