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The role of circadian clock genes in regulating the chondrogenic potential of human Embryonic Stem Cells


Project Description

Osteoarthritis (OA) is one of the most common joint diseases, affecting ~6 million people in UK, causing severe pain, deformity and a loss of mobility. A common feature of OA is the degeneration and loss of articular cartilage and chondrocytes, the only cell type in this tissue. The current clinical treatment for OA is restricted to symptomatic pain relief. The Meng group has recently identified cell autonomous circadian clocks in cartilage tissue, which controls ~600 rhythmic cartilage target genes, many of these genes have previously been implicated in diseases such as OA (Gossan et al., 2013, Arthritis and Rheumatism). hESC, due to their unlimited capacity for self renewal and pluripotency, provide a potential source of chondrocytes to be used in regenerative medicine towards joint diseases such as OA. The Kimber group has developed a novel three stage chemically defined protocol to generate chondrogenic cells from a number of hESC lines and induced pluripotent cells (Oldershaw et al 2010 Nature Biotech 28,117 and Cheng et al Tiss Eng 2013). hESC can be induced to generate a 94-97% chondrogenic population expressing SOX9, collagen type IIα1 (COL2A1) and aggrecan in vitro within 14 days.

In collaboration with the Kimber group, we have recently identified profound changes of circadian clock genes during the chondrogenic differentiation of hESC. We are particularly interested in the role of clock genes in chondrogenesis. Such understanding may help identify key niche factors, which may be harnessed to manipulate differentiation of hESC towards regenerative medicine as well as control clock function.

In this project, we are going to use genetic manipulation of hESC, in vitro chondrogenic differentiation, gene expression studies, real-time clock reporter techniques, lentiviral transduction and RNAseq approaches to address the functional significance of circadian clock genes in hESC differentiation. Exploiting the knowledge of circadian clock control will allow us to generate functioning and native-like cartilage tissue for therapeutic use as well as suggesting new disease models and drug targets for improving in vivo and in vitro matrix formation.

Funding Notes

This project has a Band 2 fee. Details of our different fee bands can be found on our website. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. Informal enquiries may be made directly to the primary supervisor.

References

Gossan N, Zeef L, Hensman J, Hughes A, Bateman JF, Rowley L, Little, CB, Piggins HD, Rattray M, Boot-Handford RP, Meng QJ, (2013). The circadian clock in chondrocytes regulates genes controlling key aspects of cartilage homeostasis. Arthritis and Rheumatism; Epub ahead of print.

Meng QJ, Maywood E, Bechtold D, Lu WQ, Li J, Gibbs J, Dupré S, Chesham J, Rajamohan F, Knafels J, Sneed B, Zawadzke L, Ohren J, Walton K, Wager T, Hastings M, Loudon A (2010) Entrainment of disrupted circadian behavior through inhibition of Casein Kinase 1 (CK1) enzymes. Proceedings of the National Academy of Sciences of the United States of America, 107 (34), 15240-15245.

Oldershaw RA, Baxter MA, Lowe ET, Bates N, Grady LN, Brison DR, Hardingham TE & Kimber SJ. 2010. The directed differentiation of human embryonic stem cells towards chondrocytes Nature Biotech 28, 1187-1193

Soteriou D, Iskender B, Byron A, Borg-Bartolo S, Haddock M-C, Baxter M, Humphries, JD, Knight D, Humphries MJ, and Kimber SJ. (2013) Comparative Proteomic Analysis of Supportive and Unsupportive Extracellular Matrix Proteins for Human Embryonic Stem Cell Maintenance J Biol Chem 288, 18716-18731

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