Research projects

• BHF 4 year PhD Studentship programme

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Deciphering disease mechanisms underlying hypertensive pregnancy

Supervisors: Delyth Graham, Martin McBride

Project outline: The incidence of cardiovascular disease amongst women of child-bearing age is increasing. Consequently there is a greater prevalence of hypertensive disorders in pregnancy, in particular pre-eclampsia (PE), which is a leading cause of maternal and foetal morbidity and mortality. Despite its increased prevalence, the mechanisms underlying key pathological features of the disease remain unclear, and there are currently no effective clinical interventions.

The stroke prone spontaneously hypertensive rat (SHRSP) is an established model of human cardiovascular disease, which exhibits chronic hypertension during pregnancy1. This model can be progressed to the more severe pregnancy complication, superimposed PE, through angiotensin II administration mid-gestation2. Our recent studies in this model have identified pregnancy- and disease- dependent alterations in the uterine artery transcriptome relative to the normotensive control strain3. 

In this project, the specific molecules and pathways identified in our previous SHRSP studies will be explored mechanistically to determine their role in the pathogenesis of hypertensive pregnancy in order to identify new targets of therapeutic or diagnostic interest.

Techniques used: The student will receive training in a wide range of techniques, including animal models of hypertension and PE, cell culture, imaging, molecular biology approaches as well as RNASeq and other ‘Omics’ datsets and bioinformatic and pathway analysis. This PhD project will provide opportunities to develop an almost unique combination of in vivo, in vitro and molecular skills set.

References:

1. Small HY, Morgan H, Beattie E, Griffin S, Indahl M, Delles C, Graham D. Abnormal uterine artery remodelling in the stroke prone spontaneously hypertensive rat. Placenta. 2016 Jan;37:34-44.
2. Morgan HL, Butler E, Ritchie S, Herse F, Dechend R, Beattie E, McBride MW, Graham D. Modeling Superimposed Preeclampsia Using Ang II (Angiotensin II) Infusion in Pregnant Stroke-Prone Spontaneously Hypertensive Rats. Hypertension. 2018 Jul;72(1):208-218.
3. Scott K, Morgan HL, Delles C, Fisher S, Graham D, McBride MW. Distinct uterine artery gene expression profiles during early gestation in the stroke-prone spontaneously hypertensive rat. Physiological Genomics, 15 Mar 2021, 53(4):160-17
   

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Developing gene therapy approaches for stroke, eye and kidney disease due to mutations in collagen

Supervisors:  and Mark Bailey (SoLS)

Mutations in collagen IV cause a severe genetic disorder that includes brain bleeding, eye and kidney disease. In addition rare mutations also contribute to stroke in the general population. There are no treatments available for these disease, and the complex nature of the disease further hinders treatment development.

A gene therapy based approach is therefore an attractive solution to develop a potential cure for this disease.

Using a panel of cell lines from patients and endothelial cells with mutations, you will investigate different gene therapy approaches to silence the expression of collagen IV mutations. This would involve developing different strategies and introduce them into cell culture to determine if they can overcome the cell defects of these mutations. If successful this could be translated into treatments for our animal models of diseases due to collagen mutations.

Techniques used: You will use a large variety of molecular biology approaches for the design and cloning of gene therapy approaches, cell culture, analysis of endothelial cell function (eg. angiogenesis assays), biochemical and molecular analysis, imaging etc.

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Developing Therapeutic approaches for haemorrhagic stroke

Supervisor: Dr. Tom Van Agtmael

Research area: Mouse genetics, haemorrhagic stroke, molecular cell biology, extracellular matrix, vascular disease, collagen, endoplasmic reticulum stress

Project outline: Stroke costs UK Society ~£8 billion annually with haemorrhagic stroke accounting for 15% of adult and 50% of paediatric stroke. There are no treatment available for haemorrhagic stroke, in part due to a poor understanding of the underlying molecular cause.
Collagen IV is the major component of a type of extracellular matrix called the basement membrane that provides essential structural support to blood vessels. We and others have shown that mutations in COL4A1 or COL4A2 (encoding collagen IV proteins) cause familial and sporadic haemorrhagic, indicating these mutations may be more common than previously expected and a potential contribution to stroke in the general population (1). Our results also reveal that endoplasmic reticulum (ER)-stress due to intracellular accumulation of mutant collagen IV is associated with disease development, and that treatment of collagen IV mutant cells can reduce ER-stress (2). This provides a golden opportunity to identify the disease causing mechanisms and explore therapeutic approaches for collagen IV diseases including haemorrhagic stroke.
We have brought together a unique cohort of cell lines from patients and animal models with Col4a1 mutations to investigate the disease mechanisms of these mutations and determine how cells respond to these mutations. The identified pathways will then be modified in cell line and animal models to investigate their role in disease development and identify their potential as a therapeutic target. As FDA approved compounds are available, this will directly inform on and may identify therapeutic approaches for haemorrhagic stroke.

Project aims:

• Exploring genetic and high throughput approaches to identify pathways that influence disease development
• Identify the ability of small compounds to prevent the pathological effects of collagen IV mutation in cells.
• Modification of disease development in animal models

Techniques used: State of the art imaging techniques including 3-dimensional electron microscopy, confocal microscopy and atomic force microscopy. Molecular cell biology, animal models, MRI imaging, transcriptomics.

References:

• Plaisier E, et al. Role of COL4A1 Mutations in the Hereditary Angiopathy with Nephropathy, Aneurysm and Cramps (HANAC) Syndrome. New Eng J Med 2007, 357, 2687-2695
• Murray LS et al. Chemical chaperone treatment reduces intracellular accumulation of mutant collagen IV and ameliorates the cellular phenotype of a COL4A2 mutation that causes haemorrhagic stroke. Hum Mol Genet 2014, 23:283-92

Contact address and email:

tom.vanagtmael@glasgow.ac.uk
Dr. Tom Van Agtmael
School of Cardiovascular and Metabolic Health
College of Medical, Veterinary and Life Sciences
Davidson Building
University of Glasgow
University Avenue
Glasgow, G12 8QQ
United Kingdom
Phone: +44 (0)141 330 6200

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Investigating disease mechanisms of collagen IV disease including intracerebral haemorrhage

Supervisors: and Alyson Miller

15% of strokes are due to intracerebral haemorrhage (ICH), for which there is no treatment. and absence of specific effective treatments indicates increased knowledge of its pathomolecular basis is required. Recent genetic data has identified an important role for the protein collagen IV in stroke due to haemorrhage. Mutations in collagen IV also cause eye, kidney and muscle disease for there are also no treatments. We and others have showed the mutations and variants in collagen can cause defects to the extracellular matrix as well as a cell stress response called ER stress.

This project will use a powerful set of bespoke mouse models to determine in vivo the relative contribution of BM defects and ER stress to ICH as well as eye and kidney defects due to collagen IV. This will be combined with vascular physiology and molecular approaches, including transcriptomics and/or proteomics, to identify novel mechanisms.

Importantly, you will validate these mechanisms in patients. This project can be tailored to the interests of the candidate but will transform our knowledge of molecular mechanisms of stroke and disease due to collagen. This will aid development of precision medicine treatments.

Techniques used: you will be trained in a large variety of techniques crossing animal models of stroke, analysis of vascular function, molecular and biochemical approaches, imaging etc.

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Personalised management of blood testing for renal function in patients with and without diabetes

Supervisors: Paul Welsh and Patrick Mark

The management of chronic diseases, including diabetes, accounts for 50% of clinical biochemistry testing. The number of clinical biochemistry tests requested is estimated to have increased by 10% annually for the last two decades. This has been due to a combination of complex clinical and management factors. However, there is a paucity of evidence that frequent testing actually improves patient care or alters clinical outcomes.

Scottish clinical guidelines for screening for kidney disease in diabetes patients states that estimated glomerular filtration rate and albumin-creatinine ratio should be assessed on an annual basis in people with diabetes, and that more frequent assessment may be necessary in adults with established chronic kidney disease (CKD). The guidance is similar in England and Wales. It is not clear how well these guidelines are adhered to in clinical practice. Beyond this, the evidence supporting this approach is derived from a health economics focused meta-analysis of randomized controlled trials, but does not take account previous measurements. For instance, those with good renal function may not require frequent re-testing.

Outside of the diabetes field, population based screening for renal function is not currently recommended. NICE guidelines suggest testing kidney function in people with risk factors for CKD such as hypertension, systemic disease (e.g. systemic lupus) or a family history of kidney failure. Anecdotal evidence from several sources suggests large numbers of creatinine tests are conducted in routine clinical practice. A data science approach might improve the evidence base for renal function testing for both targeting those at highest risk and optimizing follow-up. Furthermore, although blood testing for kidney function is widespread, measurement of urinary albumin to creatinine ratio is performed infrequently despite being a stronger predictor of cardiometabolic risk. Risk assessment tools exist but these were validated in populations with known CKD (not the general population) and do not account changes in risk factors over time. They are not in widespread use in the UK.

This project will explore the patterns of renal function testing in the NHS Greater Glasgow and Clyde area (>1million patients) and investigate evidence that might support an optimised approach to renal function testing in the general population and people with diabetes.

Training outcomes:
1. Experience in the use of medical statistics as applied to electronic health records, with further training if required.
2. Proficiency in the use of statistical software for medical statistics.
3. Conduct of systematic reviews of clinical guidelines.
4. Knowledge and experience of the structure of data in, and governance framework for, electronic health records as they relate to research.
5. Knowledge of the clinical guidelines for blood monitoring in chronic disease in the UK.
6. The student will also attend chronic disease review clinics; an established pathway under our flagship Clinical Observership Programme for basic scientists in our School.

References

1. Smellie WSA. Demand management and test request rationalization. Ann Clin Biochem 2012; 49: 323–323
2. https://www.nice.org.uk/guidance/cg182/resources/chronic-kidney-disease-in-adults-assessment-and-management-pdf-35109809343205
3. National Institute for Health Care and Clinical Excellence. Chronic kidney disease in adults: assessment and management. Clinical guideline [CG182].
4. Tangri N, Stephens LA, Griffith J et al A Predictive Model for Progression of Chronic Kidney Disease to Kidney Failure. JAMA. 2011;305(15):1553-1559.

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Runx1 and Heart Failure

Supervisor: Dr C Loughrey, Dr S Nicklin, Ewan Cameron

Research area: Heart research

Project outline: Coronary heart disease (CHD) leading to myocardial ischaemia is the predominant cause of heart failure (HF) and premature mortality in the UK. CHD occurs when the blood vessels of the heart (coronary arteries) become narrowed by fatty material (atheroma) and reduce blood flow to heart muscle (myocardial ischaemia). If the coronary artery is occluded then an area of lethal tissue injury in heart muscle called a myocardial infarction (MI) can be produced. The subsequent structural and functional changes in the surviving heart muscle can lead to poor cardiac pump function and HF. Novel therapeutic strategies to preserve cardiac pump function are urgently needed to treat patients with myocardial infarction and thereby improve patient survival rates and quality of life.

The Runx family of genes (Runx1,2&3) encode for DNA binding transcription factors (Runx1,2&3) which regulate gene expression. Recently, increased Runx1 expression has been demonstrated in the hearts of patients with MI. In line with these data, our recent work demonstrates increased Runx1 expression in a mouse model of MI.

However, despite these observations, the role Runx1 plays in heart function remains unknown. We have made a novel and exciting discovery that higher Runx1 expression levels correlate with poor cardiac pump function. In order to corroborate this finding, we have produced a heart-specific knockout of Runx1. When MI is induced in this transgenic model, cardiac pump function is markedly improved suggesting that reducing Runx1 expression in the heart is a novel therapeutic approach to limit the progression of cardiac dysfunction in patients with MI.

Project aims: This studentship will investigate the relationship between Runx1 expression in the heart and the development of heart failure. In addition, the project will develop therapeutic strategies to reduce Runx1 expression in cardiac disease in order to prevent progression to heart failure.

Techniques used: The project will enable the student to be trained in in vivo rodent models of heart disease, integrative physiology, molecular biology and gene therapy approaches.

References:

• Cardiovascular Research, Volume 116, Issue 8, 1 July 2020, Pages 1410–1423, https://doi.org/10.1093/cvr/cvaa034

Contact email: christohper.loughrey@glasgow.ac.uk

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Understanding the causes and consequences of diabetes and cardiovascular diseases in UK Biobank

Supervisors: Paul Welsh and Naveed Sattar

UK Biobank is a uniquely large and well characterised prospective cohort study of ~500,000 adults in middle-age living in the UK. The study now has around 15 years of follow-up available and there is forthcoming linkage of all participants in the cohort to primary care data. This presents a unique opportunity to investigate the causes and consequences of many less common diseases (such as aortic aneurysms), and common diseases diagnosed in primary care (such as type 2 diabetes and dementia).

This flexible project presents an opportunity to the interested student to help design their own portfolio of data-driven work, and to be more widely involved in our highly successful UK Biobank working group which has led several seminal publications on the cohort 1-5. With experienced supervisors, the student can develop the area of interest and identify aims of interested based on literature review, and using this world-class data set and existing resources we have developed.

Training outcomes:

1. Experience in the use of medical statistics, including further training in medical statistics if required.
2. Proficiency in the use of statistical software for medical statistics.
3. Conduct of systematic reviews of the literature.
4. Knowledge and experience of the structure of electronic health care records in the UK.

References:

1. Welsh C, Celis-Morales CA, Ho F, Lyall DM, Mackay D, Ferguson L, Sattar N, Gray SR, Gill JMR, Pell JP, Welsh P. Association of injury related hospital admissions with commuting by bicycle in the UK: prospective population based study. BMJ. 2020 Mar 11;368:m336.
2. Welsh C, Celis-Morales CA, Brown R, Mackay DF, Lewsey J, Mark PB, Gray SR, Ferguson LD, Anderson JJ, Lyall DM, Cleland JG, Jhund PS, Gill JMR, Pell JP, Sattar N, Welsh P. Comparison of Conventional Lipoprotein Tests and Apolipoproteins in the Prediction of Cardiovascular Disease. Circulation. 2019 Aug 13;140(7):542-552.
3. Lees JS, Welsh CE, Celis-Morales CA, Mackay D, Lewsey J, Gray SR, Lyall DM, Cleland JG, Gill JMR, Jhund PS, Pell J, Sattar N, Welsh P*, Mark PB*. Glomerular filtration rate by differing measures, albuminuria and prediction of cardiovascular disease, mortality and end-stage kidney disease. Nat Med. 2019 Nov;25(11):1753-1760
4. Welsh C, Welsh P, Celis-Morales CA, Mark PB, Mackay D, Ghouri N, Ho FK, Ferguson LD, Brown R, Lewsey J, Cleland JG, Gray SR, Lyall DM, Anderson JJ, Jhund PS, Pell JP, McGuire DK, Gill JMR, Sattar N. Glycated Hemoglobin Prediabetes, and the Links to Cardiovascular Disease: Data From UK Biobank. Diabetes Care. 2020 Feb;43(2):440-445.
5. Celis-Morales CA, Welsh P, Lyall DM, et al. Associations of grip strength with cardiovascular, respiratory, and cancer outcomes and all cause mortality: prospective cohort study of half a million UK Biobank participants. BM 2018 May 8;361:k1651.

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Uromodulin a Precision Medicine Target for Novel Drug Discovery in Cardiovascular Disease

Supervisors: Delyth Graham, Martin McBride

Background: Despite major advances in cardiovascular health, hypertension remains the risk factor contributing most to the overall burden of disease globally. When the total global impact of known risk factors on the overall burden of disease is calculated, 54% of stroke and 47% of ischaemic heart disease are attributable to hypertension.

In our recent genome-wide association study using an extreme case-control design, we discovered a SNP (rs13333226 at position 16:20365654) in the 5’ region of the Uromodulin gene (UMOD), also known as Tamm-Horsfall glycoprotein (THP) to be associated with hypertension. The minor G allele of rs13333226 was associated with lower risk of hypertension, decreased urinary uromodulin excretion, and higher glomerular filtration rate. Furthermore, the association with hypertension was shown to be independent of renal function indicating a possible pleiotropic effect, as SNPs highly correlated with rs13333226 were shown to be associated with kidney function in independent GWAS studies. The genotype association of rs13333226 and urinary UMOD excretion was more pronounced with low salt intake, and blunted with high salt intake, indicating a possible gene-environment interaction.

We have extended these findings with work in UMOD KO mice which show a lower baseline blood pressure and are not sensitive to salt induced changes in blood pressure. Our data indicate that UMOD has a role in BP regulation and may protect from salt induced increase in BP. UMOD is selectively produced in the thick ascending limb of the loop of Henle in the kidney. and exists predominantly as a polymer in luminal fluid.

Proposal Plan: Molecular characterisation of human and mouse uromodulin transcripts and binding partners.

In this project, we will utilise RNA from a large panel of human kidneys (~100) grouped according to hypertension status, as well as the UMOD knock out mouse. We have access to human and rodent RNAseq data that we will analyse using different strategies including biological pathways using gene set enrichment and Ingenuity Pathway Analysis. We are also interested in identifying binding partners of UMOD under different environmental stressors and assessing potential transcription factor binding in the promoter region using Electrophoretic Mobility shift Assays (EMSA).

Project aims

• Assess humanUMOD transcripts using RNAseq  Explore biological pathways using Ingenuity Pathway Analysis. 
• ValidateRNAseq gene expression changes using our panel of human kidneys prioritised by pathway analysis. 
• Use immunoprecipitation and mass spectrometry to identify binding partners of UMOD in human renal tissueto characterise potential mechanisms of action in disease.
• Assess the genetic contribution of UMOD in large scale data including UK Biobank

Techniques used: 

• Isolation ofDNA and RNA 
• qRT-PCR and Sanger sequencing
• PCRand cloning 
• Western analysis
• AnalysingRNAseq transcript data and other ‘Omic’ platforms
• Biological pathway and data integration analysis
• Electrophoretic Mobility ShiftAssays to identify potential binding partners of uromodulin and assess potential binding of predicted transcription factors using mass spectrometry. 

References:

1. Small HY, Morgan H, Beattie E, Griffin S, Indahl M, Delles C, Graham D. Abnormal uterine artery remodelling in the stroke prone spontaneously hypertensive rat. Placenta. 2016 Jan;37:34-44.
2. Morgan HL, Butler E, Ritchie S, Herse F, Dechend R, Beattie E, McBride MW, Graham D. Modeling Superimposed Preeclampsia Using Ang II (Angiotensin II) Infusion in Pregnant Stroke-Prone Spontaneously Hypertensive Rats. Hypertension. 2018 Jul;72(1):208-218.
3. Scott K, Morgan HL, Delles C, Fisher S, Graham D, McBride MW. Distinct uterine artery gene expression profiles during early gestation in the stroke-prone spontaneously hypertensive rat. Physiological Genomics, 15 Mar 2021, 53(4):160-17
   

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Overview

The School of Cardiovascular and Metabolic Health is a successful and vibrant research School with outstanding training and learning opportunities. Our purpose-built British Heart Foundation (BHF) Cardiovascular Research Centre houses state-of-the-art laboratories and facilities and we are one of only six BHF Centres of Excellence in the UK.

Our research strengths have been integrated into substantial, well-resourced thematic programmes that build on the strengths of individual, clinical and non-clinical principal investigators. Working in basic, translational and clinical research, our strength is in elucidating mechanisms of cardiovascular disease, identifying biomarkers of disease, identifying therapeutic targets and developing and designing novel therapeutic strategies that will lead to clinical trials.

Individual research projects are tailored around the expertise of principal investigators within the institute. Basic and clinical projects are available for study. A variety of approaches are used, including molecular biology, biochemistry, epidemiology, mathematical modelling, bioinformatics, genetics, cell biology (including advanced in vitro and in vivo imaging), immunology and polyomics (genomics, transcriptomics, proteomics, metabolomics etc).

Specific areas of interest include:

• vascular science and medicine
• cardiovascular biology and cell signalling
• cardiovascular gene therapy for the treatment of vascular disease
• basic and clinical cerebrovascular disease e.g. stroke 
• stem cell therapies for cerebrovascular disease
• genetics, genomics and systems medicine 
• adrenal corticosteroids in cardiovascular disease
• diabetes, obesity, metabolic and renal disease
• cardiovascular imaging
• cardiovascular clinical trials
• sport & exercise science & medicine

Study options

PhD

• Duration: 3/4 years full-time; 5 years part-time

Individual research projects are tailored around the expertise of principal investigators.

Integrated PhD programmes (5 years)

Our Integrated PhD allows you to combine masters level teaching with your chosen research direction in a 1+3+1 format. 

International students with MSc and PhD scholarships/funding do not have to apply for 2 visas or exit and re-enter the country between programmes. International and UK/EU students may apply.

Year 1

Taught masters level modules are taken alongside students on our masters programmes. Our research-led teaching supports you to fine tune your research ideas and discuss these with potential PhD supervisors. You will gain a valuable introduction to academic topics, research methods, laboratory skills and the critical evaluation of research data. Your grades must meet our requirements in order to gain entry on to a PhD research programme. If not, you will receive the masters degree only.

Years 2, 3 and 4

PhD programme with research/lab work, completing an examinable piece of independent research in year 4.

Year 5

Thesis write up.

MSc (Research)

• Duration: 1 year full-time; 2 years part-time

MD (Doctor of Medicine)

• Duration: 2 years full-time; 4 years part-time (for medically-qualified graduates only)