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Endothelial senescence and healthy ageing


Project Description

Endothelial senescence is a key biological mechanism in the development of coronary artery disease and ageing. Endothelial cells line all blood vessels and control vascular homeostasis as well as forming a barrier layer preventing other cells, modified lipids, bacteria, viruses and other noxious products from gaining entry into vessel walls. Endothelial cellular senescence is a process whereby cells cease dividing and undergo distinct phenotypic, physical and secretome alterations. In this process, the cells become flatter, enlarged, cease to divide and exhibit polyploidy. The accumulation of these senescent endothelial cells in human diseased arteries has been detected and is thought to be associated with cell apoptosis, cytoskeletal rearrangement and increasing cell stiffness. Cell stiffness leading on to arterial/vascular stiffness is a characteristic of advanced coronary artery disease and is a strong independent predictor of cardiovascular morbidity and mortality, ageing, hypertension and end stage renal disease.

There are many molecular and cellular mechanisms linked to senescence and ageing such as cell cycle dysregulation, oxidative stress, calcium signalling, mitochondrial dysfunction, DNA repair, sirtuins, Klotho etc to describe a few. In addition, inflammation is important, especially interleukin-1 (IL-1) and its activation mechanisms such as the NLRP3 inflammasome. In a seminal Science paper in 1990, Maier et al. showed that an antisense oligonucleotide against interleukin-1 alpha could inhibit endothelial senescence. The hypothesis for this project is that IL-1 inhibitors reverse senescence in human endothelial cells and human mesenchymal stem cells. The project will involve in vitro work on the culture of human endothelial cells and stem cells, numerous methods to senesce these cells in culture and the use of state-of-the-art inhibitors to reverse this process. The student will also study the molecular mechanism for the observed effects and if time allows be able to test the inhibitors in an in vivo model of ageing. The outcome of the project will be to define targetable mechanisms to block endothelial and stem cell ageing which could lead to prolongation of a healthy life span.

Funding Notes

Funding:
This project is suitable for a self-funded student or a student with a government scholarship including from overseas.

Entry Requirements:
Candidates must have a first or upper second class honors degree or significant research experience. (add any additional requirements here)

The candidates must have completed a laboratory based project as part of their degree.

References

Proposed start date: October 2020

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