Completed Genetics & Molecular Biology Cancer

A mammalian genetic model for the role of short telomeres in disease.

Funder Wellcome Charity-funded
Recipient organisation University of Edinburgh
Funding £1.4M
Period Jul 2008 — Feb 2018

In plain English

AI plain-English summary

Every time a cell divides, the protective caps on the ends of its chromosomes—telomeres—get a little shorter, and when they become too short, cells stop dividing or become unstable. This project uses genetically engineered mice to test whether limiting the enzyme that rebuilds telomeres, called telomerase, accelerates the stem cell decline and genetic damage seen in ageing. The researchers will also combine this with other mutations that cause genomic instability, to see how short telomeres interact with other ageing processes. They plan to test a drug from Geron that aims to reverse the effects of telomere shortening. Finally, they will use retroviral tagging to hunt for unknown genes that become misregulated when telomeres are compromised. This is fundamental science—it will not produce a treatment tomorrow. But understanding how telomere dysfunction drives age-related diseases such as cancer, heart disease, and neurodegeneration could eventually point to new drug targets or diagnostic markers. Similar fundamental work on telomeres and telomerase has already spawned clinical trials for cancer vaccines and regenerative therapies.

View original technical description
We plan to examine the impact of telomere loss-of-integrity in a genetic setting where the capacity to upregulate TERT is retained. Firstly, we plan to ascertain whether limiting telomerase function exacerbates (or protects against) the decline in stem cell function and increase in genetic instability observed during mammalian ageing. Secondly, we plan to combine our model of limiting telomere function (heterozygosity of mTert) with other genetic backgrounds that promote genetic instability, to determine the impact of changes in telomere length associated with limiting telomerase. We also plan to attempt to reverse the phenotypes associated with telomere shortening using a novel therapeutic compound in development at Geron. Lastly, we plan to undertake an unbiased genetic approach, using retroviral tagging, to identify novel chromosomal loci whose altered regulation might contribute to genetic instability when telomere function is limited. Taken together, these studies are designed to elucidate the genetic and epigenetic modifiers of telomere function in vivo, and how these changes impact on the propensity to age-associated diseases in mammals.

View the original record at the funder ↗

Researchers

Adrian Bird (EPMC Awardee)Lea Harrington (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

When there is not enough telomerase: telomerase insufficiency and genome integrity
Role of homologous recombination activities and shelterin components in telomere replication and elongation
Identification of molecular link between telomeres and telomerase and investigation of the mechanism underlying telomerase recruitment and activation
Telomere metabolism in Genome Stability and Disease
Functional dissection of the genetic interaction network that affects growth of cells with telomere defects: implications for health and disease

Original classification

Programme Grant

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