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Impact of normal and premature ageing on human macro- and microvasculature

About This PhD Project

Project Description

The global population is growing, with the number of births consistently higher than the number of deaths. This is because people are living for longer, due at least in part to improved lifestyle and healthcare provision. Consequently, in the UK 18% of the population are aged 65 or above. This equates to almost 12 million people thus factors relating to ageing health are of prime concern. In parallel with the increasing age of the population, we also have an increase in the number of individuals with Type 2 diabetes (T2D). This presents with features of premature ageing, and currently there are over 4 million patients in the UK alone with this disease, with a further 550,000 patients with T2D but without a formal diagnosis.

Problems with blood vessels are common to both ageing and T2D. These complications include the large blood vessels (macrovasculature), for example the development of atherosclerosis, and the smaller vessels (microvasculature) that can lead to issues such as poor wound healing. Another feature common to both ageing and T2D is systemic inflammation. This has led to an emerging research field into ‘inflammaging’ which can have a negative impact on blood vessels of all types. Studies on patients with T2D have revealed that keeping tight control of blood sugar levels can improve microvascular complications; however its impact on macrovascular disease is much more contentious. There is already evidence that macrovessels have differential gene expression dependent on their vascular source and disease state (Riches et al, 2014), hence it is very likely that there will be differences between micro and macrovessels when it comes to responding to the challenges of ageing and metabolic disturbances.

Blood vessels are composed of two main cell types. Endothelial cells (EC) line the blood vessel, and smooth muscle cells (SMC) are responsible for maintaining vessel tone and are the main cellular component of the vessel wall in macrovascular arteries and veins, and microvascular arterioles. In the very fine capillaries that underlie the skin, only EC are present. Ageing can lead to EC and SMC dysfunction, as can T2D. As yet, the mechanisms leading to cellular dysfunction in both scenarios have not been fully characterised.

Gene expression differs between different vascular sources, even within the same individual. Identification of differentially expressed genes and the mechanisms leading to this will reveal new therapeutic targets to improve micro and macrovascular health in ageing and diabetes.

The aims of the project are:

1) Identify differences in the expression profile of whole vessels from different anatomical sites, with particular focus on inflammatory mediators
2) Determine cellular source of altered transcripts, e.g. EC, SMC or both
3) Determine the function and regulation of proteins from validated altered transcripts using cell culture models
4) Evaluate any impact of age and/or T2D on these proteins by comparing expression and/or activity across multiple tissue donors

This project offers a number of opportunities for developing a programme of work that can be therapeutically applied to multiple clinical scenarios e.g. cardiovascular remodelling, wound healing. It would suit a candidate with an MSc in Biology, Physiology or an allied subject.

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