Title: The role of long noncoding RNAs in the ageing of blood vessels
Funder: Dunhill Medical Trust

Abstract: The vasculature suffers significantly during ageing and a pathophysiological hallmark for this process is the accumulation of senescent endothelial cells and concomitant loss of normal repair processes (Ungvari et al., 2018). Such age-related endothelial dysfunction can cause blood vessels to become obstructed, leaky, and inflamed (Childs et al., 2015), leading to increased morbidity and mortality in older people (Wang and Bennett, 2012). In relation to this, a “Vascular Theory of Ageing” has been proposed (Le Couteur and Lakatta, 2010), and this highlights the importance of understanding endothelial cell senescence (Williamson, Stringer and Alexander, 2012). As the focus of this proposal, we will study cellular senescence in human endothelial cells as well as in vascular stem cells and their linkage to loss of normal vascular homeostasis and repair during ageing (Medina et al., 2013). Long noncoding RNA (lncRNAs) are defined as transcribed RNAs longer than 200 nucleotides that have no protein-coding potential. Emerging evidence highlights lncRNAs as a novel class of regulatory factors controlling gene expression, chromatin remodelling, molecular scaffolding, and epigenetics (Sousa-Franco et al., 2019). Recently, it has been suggested that lncRNAs play roles during the ageing process (He, Tu and Liu, 2018). Despite accounting for more than 24% of all RNA transcripts in humans, the number of lncRNAs with an assigned function is still limited (Hofmann et al., 2019). This investigation aims to advance our understanding into the mechanisms of vascular ageing and normal repair by filling a knowledge gap in relation to the role of lncRNAs in human endothelial senescence. We hypothesise that targeting expression of well-defined lncRNAs associated with endothelial senescence will lead to the development of novel strategies to promote healthy vascular ageing. We have two objectives: 1. To define the lncRNA molecular fingerprint for senescent human endothelial cells. 2. To modulate the expression of lncRNAs to increase the health span and life span of human endothelial cells.

Lay abstract: Blood vessels are the conduits that deliver oxygen and nutrients to all the cells in our body. The structural units of blood vessels are endothelial cells, which line the interior surface of arteries, veins, and capillaries. These blood vessels become obstructed with ageing, which blocks essential supply of oxygen to the heart and brain and is a major cause of disease, disability, and death in older adults. Similarly, blood vessel repair mechanisms, through vascular stem cells forming new blood vessels in damaged tissues, are also defective with ageing. This is important because evidence demonstrates that ageing of blood vessels is associated with frailty, cognitive impairment, defective wound healing, and diseases such as Alzheimer’s and atherosclerosis. At the molecular level, ageing of blood vessels is characterised by a process called cellular senescence, whereby endothelial cells lose capacity to divide and become inflamed. There is a need to increase our understanding surrounding the molecular drivers of endothelial cell senescence to enable the development of new approaches to promote healthy ageing of our blood vessels. Recent technological advances have changed the traditional concept of ‘junk DNA’, revealing its encoding function for long noncoding RNAs (lncRNAs) with an important role in disease. The biology of lncRNAs is an emerging field with many unknowns and urgent need for basic research. This investigation brings together vascular stem cell biologists working alongside mathematicians, aiming to define the role of lncRNAs in the ageing process of blood vessels. First, we will explore the changes in lncRNAs during endothelial cell senescence to identify specific lncRNA candidates that we can then modulate to increase both life span, health span, and repair capacity in human endothelial cells. This grant will fund academic research carried out by a multidisciplinary team, using state-of-the-art technologies, and human cells/tissues relevant to human ageing, to advance our knowledge on molecular mechanisms of ageing in blood vessels related to lncRNAs. We expect to identify specific lncRNAs that control ageing in human endothelial cells, with potential to lead to the development of novel strategies to improve vascular health.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR