Response to mechanical stress in ageing tissue
Description: The defining qualities of our cells - their physical features and function - can be determined by their surroundings, but the tissue environment can be demanding. Just as our muscles regenerate and are conditioned by exercise to maintain health, our cells have developed mechanisms to protect against damage induced by mechanical stress. Perhaps a predictable response to increased load would be to 'bulk up' the structural components within the cell. However, changes in the regulation of metabolism, the consumption of small molecules that fuel cells and form the building blocks of growth and regeneration, could be equally crucial in repairing damage. A fundamental response to stress is the production of 'chaperone' or 'heat shock' proteins within our cells. These molecular machines act to limit and reverse damage by refolding proteins unwound by stress back into functional structures. However, these mechanisms are thought to deteriorate in old age. This loss of function may be compounded by other factors affecting aging tissue: the matrix - the material in which cells are embedded - is known to stiffen with age and the tissue has a reduced potential to regenerate its cells through mechanisms such as the proliferation of stem cells.
This proposal describes work to examine the extent to which heat shock proteins are needed to protect the cytoskeleton, the network of structural proteins that give our cells the robustness necessary to withstand mechanical stressing. It will consider the consequences of an impaired stress response, as seen in our cells as they age, by blocking or removing the activity of heat shock proteins. The effects of this perturbation will be measured in model systems that reflect the conditions found in mechanically stressed tissues such as muscle and heart. These systems will also be tuned to model the changes in matrix composition and stiffness that manifest in aging tissue. I will also examine the effects of mechanical stress and impaired heat shock response on the ability of tissue to repair itself by looking at the effect on the regenerative capacity of stems cells. By better understanding the stress response, the proteins it is designed to protect and how they alter during stress and aging, I will be able to suggest better pathways to target in developing future therapies for heart and muscle wasting. Findings of this work may also caution against inhibiting the stress response machinery when treating other diseases such as cancer in patients particularly at risk of heart disease.
In recent years, scientists have developed powerful methods to characterize the genetic programing, protein contents and metabolic activities of cells. My proposal will combine these methods with new tools, developed during my post-doctoral work, to examine protein interactions and changes in 'fold' or shape. Determining which proteins interact is particularly important for this study in order to uncover the identities of the damaged 'client' proteins that heat shock proteins are targeting. Likewise, a measure of protein fold is necessary to identify which proteins have been stressed into the incorrect shape. I will look for mechanisms of regulation by searching for protein modifications in stressed systems: chemical alterations such as phosphorylation have potential as mechano-sensitive 'flags' for signaling, whereas modifications such as oxidation may be markers of an overloaded stress response machinery. A combination of these methods will give a complete picture of the cellular response to stress and thus give a new perspective on the stiff-tissue disorders associated with old age.
Amount: £1,150,000
Funding type: fellowship
Start date: 2014-09-21
End date: 2020-11-20
Topic: Heat shock proteins research
Subfield: Molecular Biology
Domain: Life Sciences
Funded outputs count: 42
Funder award ID: BB/L024551/1
OpenAlex ID: G2410783169