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Role of telomere attrition in pancreatic beta cell dysfunction


Project Description

Type 2 diabetes (T2D) is a complex condition caused by a myriad of interacting genetic and lifestyle factors. The risk of developing T2D 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 T2D, in order to develop novel ways of predicting, preventing and treating this increasingly common age-related condition.

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 T2D, as well as insulin resistance, impaired glucose tolerance and metabolic syndrome. Shorter LTL is also associated with several known risk factors for these conditions, including obesity (see references for further background information, all are open access). However, the biological mechanisms underlying the epidemiological associations between telomere length and T2D 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 - affects pancreatic beta cell function in vitro.

The project will provide training in a wide range of cell and molecular biology techniques, including 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

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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