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Low density lipoprotein oxidation and atherosclerosis


   Department of Biomedical Sciences

   Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Project overview

The research in Professor David Leake’s group is concerned with atherosclerosis, the underlying cause of coronary heart disease and thrombotic strokes. We are investigating how low density lipoprotein (LDL), which carries most of the cholesterol in blood, is oxidised (i.e. becomes ‘rancid’) in atherosclerotic lesions. Atherosclerotic lesions are inflammatory sites and contain many macrophages. We have shown that LDL is oxidised within lysosomes in macrophages and that this oxidation is catalysed by iron at the lysosomal pH of 4.5. This oxidation increases the pH of lysosomes so that they cannot function effectively and causes the secretion of cytokines making the inflammation worse. The antioxidant cysteamine, which accumulates in lysosomes, decreases atherosclerosis in mice and even makes established atherosclerotic lesions smaller. The ultimate aim is to use antioxidants targetted to lysosomes to prevent atherosclerosis in humans.

School of Biological Sciences, University of Reading:

The University of Reading, located west of London, England, provides world-class research education programs. The University’s main Whiteknights Campus is set in 130 hectares of beautiful parkland, a 30-minute train ride to central London and 40 minutes from London Heathrow airport.

Our School of Biological Sciences conducts high-impact research, tackling current global challenges faced by society and the planet. Our research ranges from understanding and improving human health and combating disease, through to understanding evolutionary processes and uncovering new ways to protect the natural world. In 2020, we moved into a stunning new ~£60 million Health & Life Sciences building. This state-of-the-art facility is purpose-built for science research and teaching. It houses the Cole Museum of Zoology, a café and social spaces.

In the School of Biological Sciences, you will be joining a vibrant community of ~180 PhD students representing ~40 nationalities. Our students publish in high-impact journals, present at international conferences, and organise a range of exciting outreach and public engagement activities. During your PhD at the University of Reading, you will expand your research knowledge and skills, receiving supervision in one-to-one and small group sessions. You will have access to cutting-edge technology and learn the latest research techniques. We also provide dedicated training in important transferable skills that will support your career aspirations. If English is not your first language, the University's excellent International Study and Language Institute will help you develop your academic English skills. The University of Reading is a welcoming community for people of all faiths and cultures. We are committed to a healthy work-life balance and will work to ensure that you are supported personally and academically.

Eligibility:

Applicants should have a good degree (minimum of a UK Upper Second (2:1) undergraduate degree or equivalent) in Biomedical Sciences, Biological Sciences or a strongly-related discipline. Applicants will also need to meet the University’s English Language requirements. We offer pre-sessional courses that can help with meeting these requirements.

How to apply:

Submit an application for a PhD in Biological Sciences at http://www.reading.ac.uk/pgapply .

Further information: http://www.reading.ac.uk/biologicalsciences/SchoolofBiologicalSciences/PhD/sbs-phd.aspx


Funding Notes

We welcome applications from self-funded students worldwide for this project.
If you are applying to an international funding scheme, we encourage you to get in contact as we may be able to support you in your application.

References

Ahmad, F., Mitchell, R.D, Houben, T., Palo, A., Yadati, T., Parnell, A.J., Patel, K., Shiri-Sverdlov, R. and Leake, D.S. (2021) Journal of the American Heart Association 10, e017524. Cysteamine decreases low density lipoprotein oxidation, causes regression of atherosclerosis and improves liver and muscle function in LDL receptor deficient mice
Wen, Y., Ahmad, F., Mohri, Z., Weinberg, P. D. and Leake, D. S. (2019) Atherosclerosis 291, 9-18 Cysteamine inhibits lysosomal oxidation of low density lipoprotein in human macrophages and reduces atherosclerosis in mice
Ahmad, F. & Leake, D.S. (2019) J. Lipid Res. 60, 98-110. Lysosomal oxidation of LDL alters lysosome function, induces senescence, and increases secretion of pro-inflammatory cytokines in human macrophages
Ahmad, F. & Leake, D.S. (2018) Chem. Phys. Lipids 213, 13-24. Antioxidants inhibit low density lipoprotein oxidation less at lysosomal pH: A possible explanation as to why the clinical trials of antioxidants might have failed
Satchell, L. & Leake, D.S. (2012) Biochemistry 51, 3767-3775. Oxidation of low-density lipoprotein by iron at lysosomal pH: Implications for atherosclerosis
Wen, Y. & Leake, D.S. (2007) Circ. Res. 100, 1337-1343. Low density lipoprotein undergoes oxidation within lysosomes in cells
Please see Prof David Leake’s academic profile:
http://www.reading.ac.uk/biologicalsciences/SchoolofBiologicalSciences/Meetourteam/staff/d-s-leake.aspx

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