Bad to the Bone: How does the genome control when and where bone grows?

This PhD Project would suit a student inspired by the prospect of being part of a truly multidisciplinary team. This project sits at the interface between medicine, molecular biology, genomic medicine and industry, and is ideal for somebody who wishes to further core skills in molecular biology, bioinformatics and genomic medicine. You will develop skills in general laboratory medicine as well as state-of-the-art tools in exploring the molecular consequences of non-coding sequence variation. Uniquely, the iCASE placement will give you a complementary experience in deadline and target-driven clinical application development work.

What is the project about and how would you be involved?

How the body controls where and when bone is made is critical to an organism's survival and function. However, there are times when the body gets it wrong and makes bone outside of the skeleton, for example in the muscles after a severe injury to the body or head, or in heart disease, where bone can actually form within the blood vessel walls. This project is all about understanding how the genome controls this process and how epigenetics can affect that control. We have previously shown in genetic association studies that there is an inherited component to the disease, finding that differences between individuals in the long non-coding RNA gene CASC20 plays a role in disease susceptibility through its interactions with multiple microRNAs (pieces of genetic material that stop a gene working). Here we plan to find out the exact molecular mechanisms through which CASC20 makes this wrong bone formation occur.

In this DiMeN PhD studentship, you will join an interdisciplinary and cross-institutional and crucially, and industrial partnership to determine the mechanisms by which CASC20 promotes pathological bone formation, empowering us to develop novel strategies to modulate its development in diseases of ageing. Specifically, your project will address the following questions: 1) What are the downstream mechanistic target genes of CASC20? 2) Where is/are the CASC20 RNA functional sequence/s that regulate its targets? 3) What is the mechanism of the interaction between CASC20-and its associated microRNAs that results in abnormal bone formation?

What training will you receive?

We feel passionately about the opportunities that epigenetics will bring to our field of human ageing and want to transfer our enthusiasm to a student who also sees the development opportunities in this area. As well as specific training in molecular biology and genomics, you will be immersed in the biology of a common, complex disease. You will gain expertise in all these fields through the inter-institutional and through our strong industrial collaboration. You will have the opportunity to participate in the seminar and lecture series available at Sheffield and Newcastle to maximize the learning resource available. This will including a period of industrial training in Sheffield with StemcellX, as well as that received by the academic institutions.