Matrix is essential for multicellular life. It surrounds and supports cells and accounts for one third of our body mass. We believe that defining the principles that govern the two-way interaction between cells and matrix is fundamental to understanding vertebrate development, healthy ageing, and identifying why tissue failure is a major factor in most chronic diseases.
- determine the molecular basis for matrix homeostasis and how breakdown in homeostatic mechanisms (including peripheral circadian rhythms) contribute to ageing and lead to disease,
- determine how matrix controls immune responses, contributes to host protection and drives the restoration of tissue homeostasis after injury or infection, and
- define the molecular basis of the two-way dialog that exists between cells and the mechanical status of their environment.
Research directions within the Cell-Matrix Centre
Our research directions are based on the Centre's recent exciting discoveries within themes we have named ChronoMatrix, ImmunoMatrix and MechanoMatrix.
We have shown that many tissues have prominent peripheral circadian clock mechanisms that regulate matrix. These mechanisms are co-ordinated by central circadian rhythms, but drive different gene expression locally, and we propose that these mechanisms contribute to long-term matrix homeostasis and become critically altered during ageing and disease. For example, one of our recent discoveries shows that conditional deletion of the chondrocyte clock controller Bmal1 in mice causes joint pathology with disrupted cartilage (J Clin Invest)(1).
Our research has shown that matrix regulates the innate and adaptive immune system and modulates the response of tissue cells to immune signals. It is our aim to determine how matrix controls immune responses, contributes to host protection and, by integrating signals from matrix mechanics and peripheral clocks, drives the restoration of tissue homeostasis after injury or infection. One of our recent discoveries shows that T-cells activate TGFβ via integrin αvβ8 to promote resolution of inflammation (Immunity)(2).
The mechanical properties of our tissues are critically important for normal function, but how stiffness and viscoelasticity are established and maintained is poorly understood. The consequences of pathological changes in tissue mechanics is evident in musculoskeletal diseases such as: osteoarthritis, in which matrix weakening, arising from tissue pathology and ageing, leads to tissue damage and degeneration; fibrosis in which excess deposition of matrix can lead to organ failure and death; and cancer, in which stiffened matrix can promote tumour progression. One of our recent discoveries has shown that the mechanotransducing adapter proteins talin and vinculin cooperate to engage the integrin adhesion complex with the actomyosin force machinery (Nat Comms)(3).
An ambition of ours is to exploit our research discoveries to develop new approaches for the diagnosis, treatment and prevention of diseases associated with aberrant matrix production/turnover, thus supporting the Wellcome Trust in delivering on its philosophy to improve human health. The Centre, through the Faculty of Biology, Medicine and Health at the University of Manchesterand MAHSC, has the translational capacity to deliver therapeutic/diagnostic advances in key areas of unmet need, namely fibrosis, kidney disease, musculoskeletal conditions, chronic wound healing and cancer. The Centre has active projects with SMEs and larger companies including AstraZeneca, Biogelx, Bioventus, C4X Discovery, Illumina, Synapse Electroceuticals, and Unilever, which are generating a translational pipeline for diseases of matrix dysregulation.
There are currently 20 principal investigators working in the Wellcome Trust Centre for Cell-Matrix Research. You can view their personal profiles below, which contain further information on both their specialist areas of research, their contact and biography information and links to their labs.