Opportunities to modulate extracellular matrix secretion and assembly for long term health

点击翻译按钮获取中文摘要

Collagen is the most abundant structural protein in the body, making up 1/3 of our mass. It is formed into centimetre-long fibrils. This organisation gives collagen-rich tissues their differing properties (e.g. flat plywood lattices in stretchable skin and parallel bundles in rope-like tendons). Changes to collagen underpin many of the changes we associate with ageing, such as loss of skin elasticity, poor wound healing, fibrosis, susceptibility to fracture and osteoarthritis. Most people will experience reduced quality of life due to a failure of collagen maintenance. Yet, despite its fundamental importance, we still do not fully understand how synthesis of the precursor procollagen, export from the cell, assembly and maintenance of the collagen network are regulated. This programme brings together researchers from the Universities of Manchester and Bristol, with complementary expertise in key aspects of collagen biology. We have discovered new mechanisms of collagen secretion, shown that secretion and assembly of the collagen matrix is controlled by the circadian rhythm (the internal clocks in our tissues that cycle in response to day and night patterns of activity and light), and defined how the immune system modulates the repair of a collagen matrix on wounding. Now, we wish to exploit our multidisciplinary skills that include fundamental aspects of cell and tissue biology, integrated experiments using in vitro and in vivo models, circadian biology, mathematical modelling, and novel synthetic scaffolds to answer major questions in matrix biology. Working together, sharing tools, personnel, and expertise we will be able to make more impact than we could individually. We have 5 specific aims: 1. Use cells and zebrafish to determine how the precursor of collagen, called procollagen, passes through the cell. We will define the role of key protein machineries in the Golgi apparatus (the central sorting station through which everything that is secreted by cells passes). 2. Understand how transport of newly-made collagen is coordinated in space and time. We will determine how the circadian rhythm regulates the formation, holding pattern, and export of collagen. 3. Derive a mathematical framework that links information on how collagen is made to how it is used in the body. This will allow us to predict how changes to any part of the pathway that makes and assembles collagen affects other components, which we can test in cells or animals. 4. Test how the collagen network responds to damage, in injury and ageing, and test how day/night rhythm and our immune system influence this. We will make minor injuries into translucent zebrafish and use fluorescently-labelled collagen to watch how cells respond and how the collagen network is rebuilt. 5. We will produce 3D scaffolds that mimic how old and young tissues perform. We know that tissues become stiffer as we age; using custom built scaffolds we can test how young cells respond to scaffolds that resemble old tissue and vice versa.This project will also train the next generation of scientists, exposing the early-career researchers to state-of-the-art technology and equipment and to tailored training that will benefit them in their careers. Working together offers enhanced opportunities to engage with industry, clinicians and the wider public to ensure the work has the maximum impact. As well as furthering our understanding of how the collagen matrix is assembled and regulated, the programme will generate significant new tools that will benefit the wider academic community. These include new reagents that will enable visualisation of how collagen moves through the cell, new tools to define how remodelling of collagen in skin, tendon and bone occurs during development and following injury, and new synthetic scaffolds that could be used industrially or clinically to help in repair of major skin wounds, or tendon and ligament repair following injury.