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UK funding (554 605 £) : Sonde de la fonction de la kinésine-1 dans le développement des neurones par rapport à la maintenance à l’aide de la dégradation aiguë des protéines Ukri01/12/2024 UK Research and Innovation, Royaume Uni
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Sonde de la fonction de la kinésine-1 dans le développement des neurones par rapport à la maintenance à l’aide de la dégradation aiguë des protéines
| Abstract | Neurons are extraordinary cells that face huge biological challenges, not least because most neurons last a lifetime without being replaced. Neurons extend two kinds of long, fine processes that differ in their composition and function: axons and dendrites. Axons can be a metre long in a human leg. Dendrites are much shorter but are often elaborately branched. Neurons must make the right connections with other neurons via synapses, generating thought and motion, and must also communicate with muscles. Synapses can also last a lifetime, enabling us to form memories, but are rapidly remodelled to allow us to learn. To develop and then maintain neurons over decades requires constant delivery of new material, made and packaged in the cell body then transported long distances to where it is needed. This vital traffic is carried by proteins that 'walk' along protein filaments called microtubules, acting as tiny motors. Movement away from the cell body uses kinesins, such as kinesin-1. This latter role is vital since most of our lives are spent with neurons in maintenance mode, with defects leading to neurodegenerative disease and contributing to ageing. Our aim is to investigate kinesin-1's role in the development of neurons, and how it contributes to their maintenance. We will use the nematode worm, C. elegans, which is ideal for studying neurons as they develop and function in a living animal. Complete loss of kinesin-1 is lethal, so most studies have used worms with partially functional, defective kinesin-1. These worms have never had normal kinesin-1, so if a function is affected, it could be due to an underlying developmental problem, rather than something happening now. Likewise, one cannot pinpoint precisely where in the neuron kinesin-1 works. Instead, we will use an approach where we can degrade kinesin-1 rapidly at will, simply by adding a chemical to the worms. The key novelty is the ability to remove, not just hobble, kinesin-1 on a fast timescale, in worms that have developed normally up to that point. Our objectives are: To determine how acute loss of kinesin-1 at different times in development and adulthood affects worm locomotion (crawling and swimming) To investigate how kinesin-1 works with another motor—kinesin-3—to drive the movement of a vitally important cargo: dense core vesicles. To distinguish between kinesin-1's role in neuronal development and maintenance through the life of the worm. We will look in detail at PVD neurons and at the neuronal network more generally. This work will reveal when and where kinesin-1 is needed at specific times in development and identify for the first time precisely how kinesin-1 contributes to the maintenance of neuronal structure, function, and worm locomotion. Such unrivalled detail will help reveal the full impact of kinesin-1 deficit, which occurs during neurodegeneration or ageing. This research aligns with BBSRC's goals of understanding the rules of life; generating integrated understanding of health, ageing and wellbeing; and developing a highly skilled workforce. It will use transformative technologies to generate C. elegans strains that will be a valuable resource for the C. elegans research community. Our novel method of mounting C. elegans for Lattice Lightsheet microscopy will open up this microscopy method for others. Our analysis of complex particle behaviour will provide novel functional insights that will be of importance for cell biologists, neurobiologists, biophysicists and mathematicians. |
| Category | Research and Innovation |
| Reference | BB/Z517574/1 |
| Status | Active |
| Funded period start | 01/12/2024 |
| Funded period end | 30/11/2027 |
| Funded value | £554 605,00 |
| Source | https://gtr.ukri.org/projects?ref=BB%2FZ517574%2F1 |
Participating Organisations
| University of Manchester | |
| University of Edinburgh |
Cette annonce se réfère à une date antérieure et ne reflète pas nécessairement l’état actuel. L’état actuel est présenté à la page suivante : The University of Manchester, Manchester, Royaume Uni.
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