Birkbeck, University of London Featured PhD Programmes
Norwich Research Park Featured PhD Programmes
Imperial College London Featured PhD Programmes
Engineering and Physical Sciences Research Council Featured PhD Programmes
European Molecular Biology Laboratory (Heidelberg) Featured PhD Programmes

Development of treatment for Osteoarthritis by blocking metalloproteinases


Project Description

MMP13 (collagenase 3) plays a vital role in the pathogenesis of osteoarthritis (OA) because MMP13 preferentially cleaves type II collagen, the main component of cartilage, and both MMP13 levels and enzymatic activity are enhanced in OA. Transcriptional regulation of a gene is normally governed by two elements in proximal promoter where initiation of transcription occurs, and by distal enhancers that potentiate or direct specificity of a gene. Currently, very little is known about the expression of the MMP13 proximal promoter up to 3kb away from transcription start site.

Furthermore, we have recently identified a novel enhancer located upstream in the MMP13 gene, which is only expressed in chondrocytes. By unraveling the pathway that drives MMP13 expression in human and mouse, we hope to limit the increase of MMP13 expression and possibly proteolytic activity in a cell specific manner to prevent the critical connective tissue destruction seen in OA.

The regulation of a gene such as MMP13 is governed by two types of transcriptional regulatory DNA elements: promoters (core and proximal), and distal regulatory elements such as enhancers. Thus far, studies into the transcriptional regulation in the MMP13 gene have concentrated on the proximal promoter, up to 3kb away from transcription start site, where the MMP13 promoter contains multiple factor binding sites, such as a TATA box, and those for AP-1, PEA-3, and OSE-2 21 . The AP-1 members such as c-Jun/c-Fos have been implicated in the activation of MMP13 in articular chondrocyte and a Runx-2 binding site in the MMP13 proximal promoter cooperates with the AP-1 site to mediate MMP13 transcription
.
Enhancers are densely clustered aggregations of transcription factor binding motifs, and activate transcription independent of location, distance or orientation. The regulation of spatial and temporal patterns of gene transcription during development is primarily accomplished by enhancers, although those located close to core promoters are often referred to as proximal promoters . A single gene can be regulated by multiple different enhancers, each responsible for a particular aspect of expression. Enhancer regions are frequently marked by cell-type specific histone modification patterns, particularly enrichment of mono-methylation of histone H3 lysine 4 (H3K4me1) and acetylation of histone H3 lysine 27 (H3K27Ac). In addition, the majority of enhancers contain evolutionarily conserved sequences, although the depth of conservation can vary. Enhancers can be found in intronic sequences, 5’ or 3’ to the core promoter, and although they have been found over 1MB from the gene they control, recent large screens suggest that the vast majority of enhancers are located within 100kb of a core promoter, with most located within 10kb of the core promoter.
Our strategy in this PhD is to target a critical collagenase, MMP13. Our hypothesis is that by identifying the mechanisms of transcriptional control of MMP13 in chondrocytes we will identify specific pathways and methods that can be used to block MMP13 expression in a cartilage specific manner. Our specific aims are:
i. To define the enhancer expression in adult mice and in response to induction of OA.
ii. To characterise the transcription factors and the pathway that leads to expression of MMP13.
iii. To establish whether exogenous cytokine mediated MMP13 expression depends on this novel

The student will learn a number of techniques during the course of this PhD ranging from cell culture to transfection and molecular biology to generate vectors to express specifically in chondrocytes. The major task will be identifying transcription factors by EMSA ChIP seq etc. The student will have a chance to engage in in vivo models of osteoarthritis and test the effect of blocking MMPs in such a model.

The Institute of Ageing and Chronic Disease is fully committed to promoting gender equality in all activities. In recruitment we emphasize the supportive nature of the working environment and the flexible family support that the University provides. The Institute holds a silver Athena SWAN award in recognition of on-going commitment to ensuring that the Athena SWAN principles are embedded in its activities and strategic initiatives.
To apply please send your CV and a covering letter to ,

This position will remain open until a suitable candidate is found.

Funding Notes

This is a self-funded opportunity.

References

Lim NH, Meinjohanns E, Meldal M, Bou-Gharios G, Nagase H. In vivo imaging of
MMP-13 activity in the murine destabilised medial meniscus surgical model of
osteoarthritis. Osteoarthritis Cartilage. 2014 Jun;22(6):862-8.
Lo Cascio L, Liu K, Nakamura H, Chu G, Lim NH, Chanalaris A, Saklatvala J,
Nagase H, Bou-Gharios G. Generation of a mouse line harboring a Bi-transgene
expressing luciferase and tamoxifen-activatable creER(T2) recombinase in
cartilage. Genesis. 2014 Feb;52(2):110-9.
Gardiner MD, Vincent TL, Driscoll C, Burleigh A, Bou-Gharios G, Saklatvala J,
Nagase H, Chanalaris A. Transcriptional analysis of micro-dissected articular
cartilage in post-traumatic murine osteoarthritis. Osteoarthritis Cartilage. 2015
Apr;23(4):616-28.

Email Now

Insert previous message below for editing? 
You haven’t included a message. Providing a specific message means universities will take your enquiry more seriously and helps them provide the information you need.
Why not add a message here
* required field
Send a copy to me for my own records.

Your enquiry has been emailed successfully





FindAPhD. Copyright 2005-2019
All rights reserved.