Cells are physically tugging on the protein scaffold around them, and that tugging may tell the cell’s internal protein factory to change what it builds. This matters because the scaffold—the extracellular matrix (ECM)—gives tissues their strength, flexibility, and shock absorption. When the ECM breaks down or is built incorrectly, it drives diseases that affect hundreds of millions of people: osteoarthritis (roughly 7% of the global population), fibrosis (linked to 45% of deaths in Western countries), and cancer (about 8 million deaths per year worldwide). Current science knows that cells sense the ECM’s stiffness and respond, but almost nothing is known about whether that mechanical feedback reaches the Golgi—the compartment that chemically modifies ECM proteins before they are secreted. This project tests that missing link. If the hypothesis holds, it would reveal a feedback loop: cells sense tissue mechanics, adjust Golgi processing, and remodel the ECM accordingly. That could open non-invasive treatments—using exercise or mechanical loading to improve tissue quality—and inform regenerative medicine and organoid technologies, which may also reduce animal research. The work is fundamental science; practical applications would follow from a deeper understanding of how cells build and maintain the tissues that keep the body working.
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Mechano-transduction is the sensing of mechanical stimuli by cells and the conversion of this information into biochemical cues that can induce a cellular response. Often these stimuli come from the extracellular matrix (ECM), a protein scaffold that forms the structural basis of tissues and determines their properties. For example, the ECM confers tensile strength in tendons and shock absorption in cartilage. Dysfunction of ECM turnover and mechano-transduction together play a key role in the progression of numerous diseases that pose a significant burden on human health. This includes diseases such as osteoarthritis (afflicting ~7% of the global population), fibrosis (contributing to 45% of all deaths in the west) and cancer (causing ~8 million deaths globally each year). In our current ageing populations, the prevalence of these conditions is only set to increase and thus there is a growing need to understand these processes to improve preventative interventions and treatment. This proposal offers an exciting and novel line of investigation into the mechanisms underlying maintenance of tissue health, of relevance to all these diseases and other musculoskeletal disorders. The molecular composition of the ECM is highly specialised in each tissue to reflect function and is regulated and maintained by dedicated cells whose primary purpose is to synthesise and deposit ECM proteins into the tissue. During synthesis, ECM proteins pass through a cellular compartment called the Golgi, which functions as a processing plant, adding modifications to core ECM building blocks before they are secreted. These modifications change the chemistry of the proteins and consequently how they assemble in the tissue. This in turn affects the mechanical properties of the tissue and how tissue-resident cells behave. Golgi function is therefore vital to tissue health and a better understanding of the regulation of this compartment will help to decipher the mechanisms underpinning numerous diseases. One such form of regulation could come from the ECM itself. In current literature, mechano-transduction from the ECM is well-known to influence many vital cell behaviours but very little is known about the impact it has on the Golgi. My hypothesis is that cells can sense the mechanical properties of their environment and, if they need adjusting, can send signals to the Golgi directing it to change the chemistry of newly secreted ECM proteins to remodel the tissue. This proposal aims to address this gap in our knowledge and test my hypothesis by 1) demonstrating that the Golgi can respond to mechanical signals, 2) elucidating the signalling pathways linking ECM mechanics to Golgi function 3) assessing the susceptibility of the musculoskeletal system to Golgi dysfunction in the context of mechanical signalling. The knowledge gained from this proposal will improve our understanding of how cells respond to and influence their environment and how this can go wrong in disease. The work also has the potential to highlight opportunities to modulate ECM quality using load and environmental adaptations, which will support efforts to develop treatments for musculoskeletal disease and improve quality of life through non-invasive means. This will also feed into the growing fields of regenerative medicine and organoid technology, of relevance to biological engineers and translational science. These technologies also have the potential to reduce the use of animals in research and so their development is a valuable investment.
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