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Role of telomere attrition in cardiometabolic disease risk


Project Description

Common conditions such as Type 2 diabetes (T2D) and coronary artery disease (CAD) are complex disorders caused by a myriad of interacting genetic and lifestyle factors. The risk of cardiometabolic disease is also strongly influenced by increasing age. The proportion of the UK population aged over 65 is predicted to rise sharply by 2050, from one-in-six to one-in-four, with the number of people over 80 rising from three million to eight million. Thus, there is an urgent need to further characterise the cellular pathways underlying the onset and progression of age-related conditions, in order to develop novel prevention and treatment strategies.

Telomeres are the protective nucleoprotein structures that cap the ends of linear chromosomes. Vertebrate telomeres are composed of variable numbers of a tandem repeat sequence, (TTAGGG)n, bound to the shelterin protein complex. In most somatic tissues, telomeres shorten with each cell division due to the inherent properties of linear DNA replication, a process accelerated by oxidative stress.

Shorter age-adjusted mean leukocyte telomere length (LTL) is associated with increased risk of several age-related conditions, including CAD and T2D. Shorter LTL is also associated with several known risk factors for these cardiometabolic diseases, including obesity (see references for further information, all are open access). However, the biological mechanisms underlying the epidemiological associations between telomere length and disease risk are currently unknown. The overall objective of this project is therefore to investigate how telomere shortening - and associated epigenetic, gene expression and chromatin conformation changes – may contribute to the molecular pathology underlying onset or progression of cardiometabolic disease.

The project will provide training in a wide range of cell and molecular biology techniques, for example genomic qPCR to quantitate telomere length, assays to detect long-range chromatin interactions between gene promoters and regulatory genetic elements, gene knockdown and cloning methods, fluorescence microscopy and confocal imaging, western blotting, flow cytometry, cell culture and qRT-PCR to study expression of key genes.

The student will join the multi-disciplinary Diabetes and Cardiovascular Research Group (DCRG) http://sec.kingston.ac.uk/research/research-groups/drg/, which sits within the Interdisciplinary Hub for the Study of Health and Age-related conditions (IhSHA Research Centre https://www.kingston.ac.uk/faculties/science-engineering-and-computing/research/research-centres/ihsha/). As such, the student will have the opportunity to present their data to a wider research audience and to be part of a stimulating intellectual environment that includes regular journal clubs and research seminars.

Applicants should have a first or upper second class honours degree in a relevant area to the project. A Master’s degree or equivalent qualification or other evidence of research skills and experience is preferred but not essential.

Funding Notes

There is no funding for this project: applications can only be accepted from self-funded candidates

References

Short Telomeres Compromise β-Cell Signaling and Survival (2011). Guo N, Parry EM, Li LS, Kembou F, Lauder N, Hussain MA, Berggren PO and Armanios M. PLoS One 6(3):e17858

Identification of seven loci affecting mean telomere length and their association with disease (2013). Codd V, Nelson CP, Albrecht E, Mangino M, Deelen J, Buxton JL et al. Nat Genet.. 45(4):422-7.

Multiple measures of adiposity are associated with mean leukocyte telomere length in the Northern Finland Birth Cohort 1966 (2014).
Buxton JL, Das S, Rodriguez A, Kaakinen M, Couto Alves A, Sebert S, Millwood IY, Laitinen J, O'Reilly PF, Jarvelin MR, Blakemore AIF.
PLoS One. 9(6):e99133

Human leukocyte telomere length is associated with DNA methylation levels in multiple subtelomeric and imprinted loci (2014).
Buxton JL, Suderman M, Pappas JJ, Borghol N, McArdle W, Blakemore AI, Hertzman C, Power C, Szyf M, Pembrey M.
Scientific Reports. 4:4954.

Telomere attrition and diabetes mellitus (2016). Tamura Y, Takubo K, Aida J, Ararki A and Ito H. Geriatr. Gerontol. Int. Mar.16 Suppl 1:66-74.

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