Available self-funded PhD projects in the School of Medicine

Other self funded PhD projects

Evaluation of the therapeutic potential of cannabidiol in Alzheimer’s disease

Alzheimer’s disease (AD) is a complex, progressive brain disorder that results in profound cognitive impairments, particularly in memory. A key pathological feature of AD is the build-up of hyper-phosphorylated tau and formation of neurofibrillary tangles. Increasing evidence indicates that the early synaptic impairments that occur in AD correlate with accumulation of phosphorylated tau (p-tau). In healthy brain, tau is predominantly expressed on axons, however, AD-related phosphorylation of tau drives movement of tau to synapses where it impairs synaptic physiology and function.

There is currently no cure for AD, and one key unmet challenge is to develop novel drugs that prevent the early synaptic impairments that occur in preclinical stages of AD. One potential target that has been recently identified is cannabidiol, as several studies have shown that cannabidiol has powerful neuroprotective actions. In this proposed study, we aim to establish if cannabidiol has therapeutic potential by evaluating its protective actions in various established cellular models of tau-related synaptic dysfunction. This study is multidisciplinary and will utilise a range of experimental techniques including cell culture, immunocytochemistry, confocal microscopy and electrophysiology.

Subject area: neuroscience
Main supervisor: Jenni Harvey
Informal enquiries: j.z.harvey@dundee.ac.uk
Apply: Email CV with covering letter to j.z.harvey@dundee.ac.uk

The extracellular matrix remodelling and receptor activation in obesity and cardiometabolic dysfunction

Obesity-associated insulin resistance is linked to increased deposition of extracellular matrix (ECM) components, such as collagens, hyaluronan and fibronectin in insulin-responding tissues including cardiac and skeletal muscle, liver, and adipose tissue. It has been shown that excess ECM deposition can activate their cell membrane receptors triggering intracellular signalling and leading to metabolic detrimental effects. However, how fibrosis occurs and exerts its metabolic impacts on the pathophysiology of obesity and cardiometabolic dysfunction is unknown. In this project, we aim to use in vivo and ex vivo approaches to investigate how ECM-receptor signalling in insulin sensitive tissues regulates glucose and energy homeostasis and examine the therapeutic potential of blocking this pathway for reversal of the obesity-related metabolic dysfunction.

References

1. Bugler-Lamb AR, Hasib A, Weng X, Hennayake CK, Lin C, McCrimmon RJ, Stimson RH, Ashford, MLJ, Wasserman DH, Kang L. Adipocyte integrin-linked kinase plays a key role in the development of diet-induced adipose insulin resistance in male mice. Mol Metab 2021; 49:101197
2. Weng X, Lin D, Huang JTJ, Stimson RH, Wasserman DH, Kang L. Collagen 24α1 is increased in insulin-resistant skeletal muscle and adipose tissue. Int J Mol Sci 2020; 21(16):E5738
3. Hasib A, Hennayake CK, Bracy DP, BuglerLamb AR, Lantier L, Khan F, Ashford MLJ, McCrimmon RJ, Wasserman DH, Kang L. CD44 contributes to high-fat diet induced insulin resistance in skeletal muscle of C57BL/6 mice. Am J Physiol Endocrinol Metab 2019; 317(6):E973-E983

Subject area: cardiovascular/diabetes
Main supervisor: Li Kang
Informal enquiries: l.kang@dundee.ac.uk
Apply: Email CV with covering letter to l.kang@dundee.ac.uk

Metformin-associated B12 deficiency and cognitive function in Type 2 Diabetes

Metformin is the first line treatment for type 2 diabetes (T2D). T2D patients have lower vitamin B12 levels in their blood after taking metformin. It is not clear whether this decrease in vitamin B12 causes any harm. Vitamin B12 is essential to normal energy production in all cells of the body and especially cells in the brain. Our preliminary data suggest that patients who are on metformin and a B12 supplement have better cognitive function, a term referring to things like memory, the ability to learn etc., when compared to patients on metformin alone. In the current project, we plan to study whether metformin-caused B12 decline compromises cognitive function in Scottish T2D patients. The epidemic of Type 2 diabetes (T2D) in Scotland is on the rise. It is estimated that metformin is routinely prescribed to more than two hundred thousand patients with diabetes in Scotland. The association between metformin use and low vitamin B12 has been supported by many lines of evidence. Yet its clinical significance and underlying mechanisms of metformin-associated B12 deficiency still await clarifications. We have preliminary data suggesting that vitamin B12 supplementation improves cognitive function of metformin-treated T2D patients. These data are promising and if proven true, it will have massive impact in changing the treatment regime and guidance of T2D patients. However, these data were generated using the NHANES (National Health and Nutrition Examination Survey) programme, a health and nutritional study for people in the US. Whether these preliminary results hold true to people in Scotland and in the UK is unknown. Moreover, the mechanistic study of metformin-associated B12 deficiency in cell/animal model systems is limited. In the current proposed work, we plan to extend our preliminary approach and finding to Scottish population using the resources of Tayside and Fife Scottish Care Information-Diabetes Collaboration (SCI-DC). Furthermore, we propose to investigate the genetic components of the association between metformin and B12 deficiency as well as the underlying mechanisms by which metformin decreases vitamin B12 levels in model systems.

References

1. M. A. Ahmed, Metformin and Vitamin B12 Deficiency: Where Do We Stand? J Pharm Pharm Sci 19, 382-398 (2016).
2. Q. Liu, S. Li, H. Quan, J. Li, Vitamin B12 status in metformin treated patients: systematic review. PLoS One 9, e100379 (2014).
3. F. Cabreiro et al., Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 153, 228-239 (2013).

Subject areas: cardiovascular/diabetes, health and bioinformatics and genomics
Main supervisor: Li Kang
Informal enquiries: l.kang@dundee.ac.uk
Apply: Email CV with covering letter to l.kang@dundee.ac.uk

Investigating the role of redox signalling regulating anti-angiogenic factors in cardiovascular disease using organ-on-a chip and in vivo models

Oxidative stress is explicitly linked with cardiovascular disease.  Oxidative post-translational modifications (oxPTM) of receptors, enzymes and transcription factors play an important role in cell signalling. oxPTMs are a key-way in which oxidative stress can influence cell behaviour during diverse pathological settings such as cardiovascular diseases (CVD). In addition, changes in oxPTM are likely to be ways in which low level reactive oxygen and nitrogen species (RONS) may contribute to redox signalling, exerting changes in physiological responses including angiogenesis and cardiac remodelling. 

In the disease setting upsetting the redox homeostasis leads to elevation in oxidative stress and endothelial dysfunction.  In obesity and diabetes, endothelial dysfunction often precedes the clinical signs of peripheral artery disease or cardiac hypertrophy.     Understanding the redox sensitive pathways involved in the early stages of disease development is important for targeted therapy.

In this project to decipher the impact of redox signalling on endothelial function we will use a combination of in vivo and in vitro studies. The clinical setting will be mimicked using hind limb ischemia or transverse aortic constriction models.  Cutting-edge in vivo phenotyping (telemetry, laser doppler imaging, left ventricle pressure volume loop) will be applied to novel genetically modified models to understand the physiological role of redox signalling on angiogenesis in peripheral artery disease and cardiac hypertrophy. In addition, this project will utilise stem cell technology to model pathological conditions in combination with this emerging organ-on-a-chip technology to assess redox control of endothelial function via regulation of anti-angiogenic factors.  Advancing these multicellular models will pave the way for high throughput drug screening targeted at endothelial function and the redox pathways. 

This translational project will enable the student to conduct in vivo cardiovascular pre-clinical modelling in combination with in vitro 3D cell technology to interrogate molecular pathways involved in cardiovascular disease.

Subject areas: cardiovascular/diabetes, translational and cellular imaging and engineering
Main supervisor: Colin Murdoch
Informal enquiries: c.z.murdoch@dundee.ac.uk
Apply: Email CV with covering letter to c.z.murdoch@dundee.ac.uk

Investigating non-invasive laser imaging and oxidative biomarkers as an indicator of microvascular function in peripheral artery disease

Endothelial dysfunction is prevalent in obese and elderly individual and in patients who have diabetes. It is a major contributor to peripheral artery disease (PAD) which is characterised by impaired blood flow in peripheral tissues.  In the most severe form, PAD leads to critical limb ischaemia (CLI), where impaired blood flow results in a reduction in oxygenation and nutrition of peripheral tissues results in claudication or resting pain, ulcers, gangrene and in the worst-case scenario, amputation.  The current diagnosis of critical limb ischaemia uses limb pressure in combination with a clinical observation such as resting pain, foot ulcer or gangrene. Diabetes-induced neuropathy exacerbates CLI as the lack of sensation masks one of the key diagnostic factors, resting pain.  In cases of ulcers and gangrene transcutaneous tissue oxygenation (TcPO2) is used to identify the potential of healing in patients with diabetes. Endothelial function can be assessed non-invasively using a Laser Doppler technique measuring dermal microcirculation and may be an earlier predictor of severity.  Yet, currently, the technology is not readily used to assist clinical decisions made in surgery, largely because the technology has employed single point measurements that lack spatial resolution or laser imaging which can lack temporal resolution.  A new technique allows simultaneous measurement of perfusion and oxygenation (pO2) in real time (moorO2Flo).   

The overall aim of this project is to explore the feasibility of use of laser Doppler/laser Speckle contrast imaging to aid clinical assessment and limb viability in patients with critical limb ischaemia and link with biomarkers of inflammation and oxidative stress. 

Project will validate cutting edge laser technology to assess if dermal microvascular function can provide improved clinical information pre or post operation.  Determine whether Laser imaging of microvascular function can influence intra-op decisions for successful vascular/endovascular reconstruction.  Link clinical assessment with biomarkers of plasma endothelial function including inflammation (interleukins), oxidative stress (Nox, Nrf2), endothelial activation (endothelin-1) and endothelial dysfunction (eNOS).

This translational project will enable the student to conduct imaging and thermal flare assessment in humans, investigate molecular biomarkers, and validate technology for new clinical practice.

Subject areas: cardiovascular/diabetes, translational and cellular imaging and engineering
Main supervisor: Colin Murdoch, Faisel Khan
Informal enquiries: c.z.murdoch@dundee.ac.uk or f.khan@dundee.ac.uk
Apply: Email CV with covering letter to c.z.murdoch@dundee.ac.uk

Mechanism and clinical validation of glycolytic metabolites as regulators of inflammatory responses in humans

Inflammation has become a very topical area of investigation for the identification of new cardiovascular treatments. ‘Immunometabolism’ or regulation of immunity by metabolic pathways is emerging as a key new regulatory paradigm in immune cells. In previous work, the Rena lab has established that immunometabolic regulation occurs in humans in response to the diabetes drug metformin. In the current project, an exciting new collaboration with Dr Ify Mordi will allow us to investigate: (i) a hypothetical mechanism that might underlie these effects and (ii) deduce whether this mechanism is active in humans. In cell work, we have established that increasing glycolytic metabolites to levels achieved by metformin (and also exercise), is sufficient to mediate many of the anti-inflammatory effects of the drug. In follow up cell work we will exploit proteomics and available knockouts of key signalling proteins to investigate the mechanism underlying this effect. As part of this work, we will investigate the impact of changes in protein sequence encoded by SNPs in human genes. Next, we will exploit this knowledge to carry out Mendelian Randomisation (MR) to validate that glycolytic metabolites affect inflammation in humans. MR uses the random allocation of genetic variation across a population to provide insight into the relationship between a genetically-determine exposure and an outcome of interest. By stratifying large scale genotyped human cohorts MR, we will be able to deduce whether changes in glycolytic metabolites affect inflammation in humans, studying the Neutrophil: Lymphocyte ratio and C-reactive protein. This will definitively establish clinical relevance of these metabolites as inflammatory regulators.

Subject areas: cardiovascular/diabetes, health and bioinformatics and genomics
Main supervisor: Graham Rena, Ify Mordi
Informal enquiries: g.rena@dundee.ac.uk
Apply: Email CV with covering letter to g.rena@dundee.ac.uk