Harnessing protein unfolding and aggregation in mechanotransduction

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The proposed research addresses the mechanisms underlying integrin-mediated adhesion to the extracellular matrix and mechanotransduction. These mechanisms are critical for movement of cells and their assembly into tissues, during development and throughout life. We focus on the key mechanotransducing protein talin, which by linking integrins to the actin cytoskeleton can transduce mechanical force into chemical signals. It achieves this by having protein domains that act like a series of mechanochemical switches, unfolding at intracellular forces, dislodging already bound proteins and revealing new binding sites for mechanoeffector proteins. Both biochemical and molecular genetic preliminary data from the two labs points to a novel hypothesis, that self-interactions between mechanically stretched talin molecules form an 'intracellular meshwork' (ICM), which provides a stable protein super-complex that recruits additional components of integrin adhesions. Furthermore, we have evidence to suggest that both integrin and vinculin can induce talin to form the ICM, and that vinculin and specific components of the unfolded protein response machinery have an important chaperone role in regulating talin self-interactions. We propose a wide range of experiments to test our hypotheses, from structure determination, single molecule biophysics and biochemistry, to molecular genetics and advanced imaging within intact, living Drosophila. Our findings will enhance our understanding of how protein unfolding and controlled aggregation contribute to mechanotransduction and cell adhesion. This will provide important insights into how functionally important protein aggregation can become misbalanced and lead to devastating diseases such as dementia.

The beneficiaries of this study will be:
1. Pharmaceutical and Biotech industries. The increasing recognition of the importance of mechanotransduction in fitness, obesity and disease, means that our work will be relevant for these industries. They will potentially be interested in using our findings to develop new drugs and technologies for the patients described below (2-4). The improved understanding of mechanosensing that will arise from this project could lead to the design of nanoparticles that sense and respond to mechanical force. We will contact the Cambridge Nanoscience Centre to develop such technologies, benefiting the economy of the UK and strengthen our position as a world leader in drug development. (5-10 years)
2. Those wishing to develop high levels of fitness and longevity. The mechanisms of mechanotransduction are an essential part of how the body ensures that tissues can withstand the forces produced by everyday and strenuous activity. For example, increasing levels of the mechanoeffector vinculin in the heart of the model organism Drosophila extends its lifespan 150%. The improved understanding of the beneficial activities of vinculin, and its harmful activity when over active, will aid in developing fitness regimes and promoting healthy ageing. (10-15 years)
3. Patients suffering from obesity. Mechanotransduction mechanisms play an important role in sensing the amount of food in the gut. Discovering whether hereditary impairment of mechanotransduction contributes to obesity may provide new routes for treatment. (10-15 years)
4. Patients suffering from genetic disorders that affect cell adhesion, such as muscle dystrophies or Kindler syndrome. We aim to understand how talin, vinculin and specific components of the unfolded protein response work together in tissue development and function. This could for example lead to the identification of small molecules that activate vinculin and therefore strengthen cell adhesions. New drugs would be developed and applied to strengthen cell adhesions of patients with such disorders. (10-15 years)
5. Patients suffering from neurodegenerative diseases, such as Alzheimer's or Parkinson's disease, and muscle diseases such as myofibrillar myopathies, all of which are associated with the presence of protein aggregates in the affected tissues. Our proposed project aims to elucidate a process where aggregation is harnessed by the cell to mediate cell adhesion. This understanding will help improve the selectivity of treatments aimed at preventing disease-causing protein aggregation. (10-15 years)
6. Patients suffering from cancer. A vast majority of cancer deaths are caused by metastasis, the process by which cancer cells spread within the body. The invasive behaviour of cancer cells is critically regulated by mechanotransduction. Our improved understanding of mechanotransduction mechanisms will be exploited to design ways of inhibiting the metastatic capability of cancer cells. (10-15 years)
7. Organisations and Companies recruiting scientifically trained staff, including both public and private sectors. The two postdoctoral researchers funded by this work will develop their training and expertise, as well as supervising A-level, undergraduate and postgraduate students. Thus, the work will benefit a new generation of scientists. After the completion of the work, the researchers will be able to contribute to the scientific economy of the UK by applying the skills gained in the project, whether in public or private sectors.
8. The general public. Through engagement with the public through talks, websites, social media and general audience publications we seek to communicate the excitement and beauty of scientific research. Our work will involve a substantial amount of compelling images that serve as an important starting point for public engagement with biomedicine. We will submit such images to competitions (e.g. Nikon/Wellcome Trust) to reach the widest audience.