Molecular mechanisms of dynein-2 activation and transport in cilia

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.