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MRC DTP 4 Year PhD Programme: Deciphering the role of oxidative stress in cardiovascular disease using physiological and 3D cell models.


About This PhD Project

Project Description


This project is offered as part of the University of Dundee 4-year MRC DTP Programme “Quantitative and Interdisciplinary approaches to biomedical science”. This PhD programme brings together leading experts from the School of Life Sciences (SLS), the School of Medicine (SoM) and the School of Science and Engineering (SSE) to train the next generation of scientists at the forefront of international science. The outstanding biomedical research at the University of Dundee was recognised by its very high rankings in REF 2014, with Dundee rated as the top University for Biological Sciences in the UK. A wide range of projects are available within this programme crossing exceptional strengths in four key areas: Infection and Disease; Responses to Cellular Stresses; Development, Stem Cells and Neurobiology; and Big Data and Translation. All students on this programme will receive training in computational biology, mathematical biology and statistics to equip with the quantitative skills in tackling complex biological questions. In the 1st year, students will carry out 3 rotation projects prior to selection of the final PhD project.

Oxidative stress and endothelial dysfunction are major factors in cardiovascular disease such as heart failure, peripheral artery disease and preeclampsia. This PhD project will determine how these diverse oxidative modifications contribute to cardiovascular disease regulating intracellular signalling pathways. The project will combine cutting edge multidisciplinary techniques including cardiovascular physiology, genetic engineering, 3D-cell-modelling, stem cells, and proteomics.

Preeclampsia occurs in 8% of pregnancies leading to rapid hypertension and kidney dysfunction which is difficult to predict and treat. Preeclampsia shares similar risk factors as cardiovascular disease such as obesity and diabetes. Additionally, preeclampsia predisposes women to higher risk of heart failure. Recently we linked oxidative signalling with regulation of angiogenic factors in ischemia. Cells sense changes in oxidative stress through reversible changes on redox-sensitive cysteines resulting in changes in protein function, location and transcription. Understanding common oxidative stress pathways in cardiovascular disease may help elucidate the underpinning mechanisms.

This project will provide a PhD student with a wide scope of techniques. To establish proof of concept, comprehensive cardiovascular physiological assessment will take place to phenotype the disease state using cell-specific genetically models. Cutting-edge methodology assessing cardiac function via pressure volume loops and vascular function via laser Doppler and blood pressure via telemetry. Proteomic screening (TMT) developed by Dr Henderson will determine targets that undergo oxidative post-translational modifications. The redox sensitive pathways will be validated in primary cells isolated by bead technology. A combination of molecular and imaging techniques will be used to investigating the effect of redox signalling on splicing, transcription and cellular location. Cellular functional assays such as angiogenesis and migration will take place in advanced 3D cell models.

Dr Murdoch is coordinating a Horizon 2020 grant, Innovative Modelling of Placenta for Foetal Maternal Health (iPLACENTA.eu), collaborating with industry to develop new innovative ways to model and understand preeclampsia (generating 3D placenta-on-a-chip and an integrative systems biology approach). The student will benefit from exposure to translational research working in a constructive working environment. with potential to collaborate across an established EU wide network. More information can be found at https://www.iplacenta.eu/murdochlab.html or via contacting Colin Murdoch at .

References

Recent work from the lab can be found in the following references:

1. Watanabe Y, Murdoch CE, Sano S, et al. Glutathione adducts induced by ischemia and deletion of glutaredoxin-1 stabilize HIF-1α and improve limb revascularization. Proc Natl Acad Sci. 2016;(13):201524198. doi:10.1073/pnas.1524198113

2. Murdoch CE, Shuler M, Haeussler DJ, et al. Glutaredoxin-1 up-regulation induces soluble vascular endothelial growth factor receptor 1, attenuating post-ischemia limb revascularization. J Biol Chem. 2014. doi:10.1074/jbc.M113.517219

3. Murdoch CE, Chaubey S, Zeng L, et al. Endothelial NADPH oxidase-2 promotes interstitial cardiac fibrosis and diastolic dysfunction through pro-inflammatory effects and endothelial-mesenchymal transition. J Am Coll Cardiol. 2014;63(24):2734-2741. doi:10.1016/j.jacc.2014.02.572

4. McGarry DJ, Chakravarty P, Wolf CR, Henderson CJ. Altered protein S-glutathionylation identifies a potential mechanism of resistance to acetaminophen-induced hepatotoxicity. J Pharmacol Exp Ther. 2015;355(2):137-144. doi:10.1124/jpet.115.227389

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