Molecular dissection of extracellular matrix signalling and function in the human endometrium

Lead Research Organisation: University of Oxford
Department Name: Obstetrics and Gynaecology

Abstract

The proposed research is aimed at discovering how the lining of the womb, the endometrium, functions normally and why it sometimes goes wrong. Endometrial dysfunction is very common and occurs when regulation of the endometrium breaks down and leads to common conditions such as infertility, endometriosis, the menopause and menstrual problems. In other words, endometrial dysfunction affects most women at some stage in their lives. There is therefore a substantial unmet medical need for the development of effective therapeutics in the treatment of endometrial disorders. Current drugs are mostly systemic steroid hormones which are not targeted to the endometrium. This can cause unpleasant side effects which affect the quality of life and reduces compliance.

This research will focus on an important group of sticky molecules, collectively called the extracellular matrix, that surround the cells and control their behaviour. The molecules stick to receptors on the cell surface and send signals to the inside of the cells. These signals change the behaviour of the cell causing it to, for example, divide or invade. Interactions between extracellular matrix molecules and their receptors are critical for maintaining the normal function of the tissue as a whole. Sometimes these interactions go wrong and this can be a major contributory factor to the cause of many different diseases. We know that these molecules are abundant in the endometrium, and are likely to be involved in the many processes that the endometrial cells perform in order for the endometrium to function properly. We now want to understand how these molecules and their receptors control endometrial function and how they are involved in endometrial disease. Our discoveries will have implications for the design of new drugs to specifically block or bolster the action of the extracellular molecules and that are targeted to the endometrium, rather than having systemic effects. Because the extracellular matrix is present in most tissues, not just the endometrium, this research may also benefit treatments for many different diseases.

Technical Summary

The proposed research involves the application of biophysical, biochemical and molecular/cellular techniques to dissect the function of the extracellular matrix in endometrial physiology. The extracellular matrix (ECM) has a fundamental role in many cellular processes such as development, tissue regeneration and homeostasis, and the signalling properties of ECM components via the integrin family of cell surface receptors are an important conduit for ECM function. The aims of this proposal are to determine structural requirements of endometrial ECM ligands for integrin interaction and signalling, and to define the functional consequences of ECM-integrin signalling in healthy and dysfunctional human endometrium.

The proposal builds upon our previous work in the field during which we have built a platform of complimentary technologies that will realistically allow us to undertake an ambitious programme in which structural information can be effectively translated into functional analyses.

Publications

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Grewal S (2008) Implantation of the human embryo requires Rac1-dependent endometrial stromal cell migration. in Proceedings of the National Academy of Sciences of the United States of America

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Jovanovic J (2008) Fibrillin-integrin interactions in health and disease. in Biochemical Society transactions

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Kreiner M (2008) Self-assembling multimeric integrin alpha5beta1 ligands for cell attachment and spreading. in Protein engineering, design & selection : PEDS

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Mardon H (2007) Experimental models for investigating implantation of the human embryo. in Seminars in reproductive medicine

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Pereira P (2007) Solution formulation and lyophilisation of a recombinant fibronectin fragment. in European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V