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Understanding basic biological mechanisms and the development of targeted therapies


Project Description

The PhD proposal is aimed at understanding some of the fundamental mechanism(s) that control extracellular matrix (ECM) proteins and to develop new technologies and therapeutic based on changes in fibroblast gene expression profiling and surface antibodies during the development of connective tissue fibrosis. The ability to distinguish between fibroblasts lineages using antibodies and the development of resting fibroblasts into activating, matrix-producing cells, in both normal and pathological conditions, will have a significant impact on the efficacy of treatment, and the social and economic cost of a number of severe chronic degenerative diseases and on currently untreatable genetic disorders.

Regardless of the etiology, the fibrotic components of these diseases follow common underlying pathogenic mechanism resulting in excessive tissue fibrosis/scarring and loss of organ function. Although the primary cause of such pathological manifestation is not yet understood, the investigation of the cellular and molecular mechanisms that control connective tissue formation and remodelling would enable us to understand these systems, as well as, the aberration of these controls in disease states. Furthermore, such knowledge will provide key cellular and molecular targets for therapy purposes.
Major objectives of this project are therefore to:
1- To generate fibroblast lineage tracing to identify surface markers of different fibroblast lineages.
2- To test the role of macrophages in driving ECM secretion by fibroblasts
3- Develop in vivo models to examine the impact of novel fibroblast genes in connective tissues and fibrosis.
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 fibroblasts. The student will have a chance to engage in in vivo models of fibrosis and test the effect of antibodies generated commercially to ablate fibroblasts to limit the excessive deposition of ECM.

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 .

Enquiries can be sent to

Funding Notes

This is a self-funded opportunity.

References

1: Ponticos M, Papaioannou I, Xu S, Holmes AM, Khan K, Denton CP, Bou-Gharios G, Abraham DJ. Failed degradation of JunB contributes to overproduction of type I collagen and development of dermal fibrosis in patients with systemic sclerosis. Arthritis Rheumatol. 2015 Jan;67(1):243-53.
2: Sakai K, Jawaid S, Sasaki T, Bou-Gharios G, Sakai T. Transforming growth factor-β-independent role of connective tissue growth factor in the development of liver fibrosis. Am J Pathol. 2014 Oct;184(10):2611-7.
3: Lindahl GE, Stock CJ, Shi-Wen X, Leoni P, Sestini P, Howat SL, Bou-Gharios G, Nicholson AG, Denton CP, Grutters JC, Maher TM, Wells AU, Abraham DJ, Renzoni EA. Microarray profiling reveals suppressed interferon stimulated gene program in fibroblasts from scleroderma-associated interstitial lung disease. Respir Res.2013 Aug 2;14:80.
4. Li IMH, Horwell AL, Chu G, de Crombrugghe B, Bou-Gharios G. Characterization of Mesenchymal-Fibroblast Cells Using the Col1a2 Promoter/Enhancer. Methods Mol Biol. 2017;1627:139-161.

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