Wellcome Trust Centre for Cell-Matrix Research
The Wellcome Trust Centre for Cell-Matrix Research at the University of Manchester pursues advances in the understanding of extracellular matrix (ECM) biology and its contribution to human diseases. The Centre was established in 1995 and Professor Charles Streuli is the Centre's Director.
Cell-matrix research is all about how cells interact with their local microenvironment. These interactions are necessary both to control how cells actually behave and to build tissues, which are complex collections of many cell types. In our work, we are determining the molecular events that determine how cells and matrix work together.
Our discoveries are illuminating new principles about how multicellular life is organised. The extracellular matrix is the material outside of cells that creates the three dimensional structure of tissues and gives tissues their solidity. This matrix, comprising a remarkable 70% of proteins and complex carbohydrates in the body, is crucial for nearly every aspect of the way that cells behave. For example, it is essential for cell survival, cell division, cell movements and determining the exact functions that are carried out by almost all cells in the body. Both chemical interactions between the matrix proteins and cells, and mechanical forces that arise within the matrix, determine cell behaviour, and the matrix also controls our immune systems.
A key aim for the Centre is to clarify the roles of adhesion molecules, found on the exterior of cells and how they bind to and organise the ECM. These interactions ultimately affect cell behaviour and are of huge importance medically: defects in cell-ECM interactions underpin many diseases, including cancer, diabetes, heart disease, osteoarthritis, inflammatory disorders, some forms of blindness, and many genetically inherited conditions.
Our work focuses on three specific areas in cell-matrix biology that we believe will lead to a paradigm shift in our understanding of Development, Ageing, and Chronic disease. These are:
i) Cellular Matrix Microenvironment - We are using state-of-the-art approaches to uncover how altered 3D ECM organisation and cell-matrix interactions impact on cell programing and behaviour in normal tissue homeostasis and disease pathologies.
ii) Matrix Immunobiology - We are focussing on novel areas of how ECM controls the innate and adaptive immune system, host-parasite interactions, and the immunomodulatory function of mesenchymal stem cells, and how this can be exploited for therapy.
iii) Mechanobiology of Matrix - We are designing new equipment and techniques to reveal how the physical properties of ECM are determined, how they regulate cell behaviour and the formation of tissues from the nano through to the macro scale, and how altered tissue stiffness impacts on pathology.
Researchers at the Centre include:
Dr Patrick Caswell is a Wellcome Trust Research Career Development Fellow, studying integrins and signalling receptors – proteins found on a cell’s surface that enable them to interpret their physical and chemical environment. These help dictate whether a cell grows, moves, specialises or dies. Integrin proteins are found both on the cell surface and inside the cell stored in specialised compartments known as endosomes. Dr Caswell’s group look at how movement of integrins between the two locations control the signalling pathways within the cell, which determines how the cell will respond to its environment. This is important in the understanding of cancer cells that manipulate integrin trafficking to metastasise.
Dr Clair Baldock studies the structure and growth factor regulation of extracellular matrix (ECM) proteins. Many ECM molecules undergo polymerisation to form fibrillar assemblies, the novel application of structural biology and biophysical techniques is revealing exciting insights into their molecular assembly and structural organisation. We are using a range of techniques including small angle X-ray scattering (SAXS), cryo-TEM with single particle analysis and electron tomography to tease out the structural details.
Professor Tony Day leads a team of researchers studying inflammation. Inflammation is part of our body’s natural defence against infection and is required to successfully heal wounds. However, if inflammation continues unchecked (and becomes chronic) then damage to our tissues occurs; for example, as is seen in the joints of individuals with arthritis. It is our aim to better understand the molecular processes that occur during inflammatory diseases. This includes investigating the role of the innate immune system in a major form of blindness, age-related macular degeneration (AMD) and how a protective mechanism, triggered by acute inflammation, may serve to prevent cartilage and bone breakdown.
Dr Mark Travis leads research which focuses on the immune system and how it functions to detect and destroy harmful pathogens that enter the body. Upon infection, the immune system is rapidly activated, to ensure the threat is dealt with as quickly as possible. Failure to efficiently activate the immune system to deal with infections can lead to disorders such as overwhelming or chronic infection. However, in healthy individuals it is vital that the immune system is kept in a resting state to prevent tissues of the body from being attacked. If the immune system is activated inappropriately, our own organs and tissues can be attacked resulting in debilitating autoimmune diseases such as inflammatory bowel disease, diabetes and multiple sclerosis.
Dr Rachel Lennon is a Wellcome Trust Intermediate Clinical Fellow identifying the underlying mechanisms of kidney disease. Normally our kidneys are responsible for removing waste products from blood and keeping protein molecules in circulation. The presence of excess protein in urine, known as proteinuria is often an early sign of kidney disease. Dr Lennon is using mass spectrometry and proteomics to look at the interactions between cells, their signalling pathways and the ECM. By examining these interactions it is hoped that new insights and treatments into kidney disease will be found.
Dr Andrew Gilmore studies how cells commit suicide, known as apoptosis. In all multicellular organisms it is essential that cells only grow and function in the correct context within a tissue or organ. Signals from the extracellular matrix (ECM) provide these positional cues, which are essential for maintaining tissue integrity. Appropriate ECM contact not only allows cells to grow and differentiate, but it also functions as a survival factor. Cells that do not receive the correct information from the ECM undergo apoptosis, a genetically controlled suicide programme by which damaged, displaced or unwanted cells are removed. Apoptosis is an extremely efficient process, deleting cells quickly and efficiently whilst avoiding harmful inflammatory responses. The importance of ECM dependent cell survival is seen in the development of invasive carcinoma, one of the hallmarks of which is the ability of cancer cells to metastasise to distant sites within the patient. We are trying to understand how ECM derived signals regulate apoptosis, with a long-term goal of identifying how this is abrogated in cancer cells.
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