Our cells grow antenna-like projections called cilia to sense their environment, and a motor protein called dynein-2 walks along tracks inside these cilia to deliver cargo needed for sight, smell, and embryonic development. Researchers do not yet understand how dynein-2 is switched on, how it steps along its tracks, or what it looks like when it malfunctions in disease. This gap blocks efforts to treat conditions linked to faulty cilia, including sight impairment and obesity. The researcher will use powerful electron and light microscopes, combined with AI-driven image processing, to capture dynein-2 in action at the molecular level. This is fundamental science. There is no immediate clinical application. The project aims to answer basic questions about how a key piece of cellular machinery works. Similar fundamental research on motor proteins has previously underpinned advances in understanding neurodegenerative diseases and developmental disorders. If successful, this work will produce detailed molecular blueprints of dynein-2 in both healthy and disease states, and establish workflows that could be applied to study other medically important molecular machines with unprecedented depth.
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To sense their local environment and respond to stimuli, our cells grow antenna-like projections called cilia. These antennae are vital in many important sensory functions, allowing us to see, smell and to develop properly as embryos. Improper function of cilia is linked with varied diseases from sight impairment to obesity. Currently we lack a good understanding of how cilia work, and so finding ways to treat these diseases is extremely difficult. A crucial step in understanding these antennae is discovering how special components called motor proteins work within them. Motor proteins use energy to transport different components that the cell needs. A motor protein called dynein-2 can walk along microtubule tracks inside cilia carrying cargo needed for sensing and signalling. Our understanding of how dynein-2 works is currently limited and this is what I want to elucidate. I will use different types of powerful electron and light microscope and sophisticated artificial-intelligence-enabled image processing methods to study i) what dynein-2 looks like when it is working properly and when it is causing disease, ii) how dynein-2 steps along the microtubule tracks inside cilia and iii) how dynein-2 is switched on to carry its cargo. These are questions fundamental to understanding how dynein-2 and cilia function, underpinning their many physiological roles. The answers generated in this research will aid efforts to fix dynein-2 when it goes wrong in disease, and generate workflows to understand this and other medically important molecular machinery in unprecedented depth.
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