PaRTiS: Peripheral RNA Translation in Sensitisation

PaRTiS：致敏中的外周 RNA 翻译

• 批准号: BB/Y003993/1
• 负责人: Isabella Maiellaro
• 金额: $ 84.84万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY003993%2F1
• 关键词: PaRTiS; Peripheral; RNA; Translation; Sensitisation

Our bodies have a natural response to pain, which helps us avoid harmful things. When we touch something sharp, we feel pain and quickly move our hand away. This is because special nerve cells in our body detect the painful event and send a message to our brain to make us feel pain. Pain is an unpleasant feeling, but it's important because it tells us that something is wrong, and we need to take action to protect ourselves.When we get an injury, like a cut or a bruise, our body sends extra blood to the area to help it heal. This can cause the area to become swollen and painful, even after we've removed the entity that caused the injury. This is called sensitization, and it is a natural way for our body to protect the injured area while it is healing. However, sensitisation can sometimes last for a long time, even after the injury has healed, leading to maladaptive responses and chronic pain.We don't fully understand how our body co-ordinates sensitization, or what make the sensitisation last longer, but we do know that there are many different proteins involved. Some of these proteins can make the nerve cells in our body more sensitive to pain. We want to understand how these proteins work and where they are located in the nerve cells, so that we can find ways to stop chronic pain from happening.Nerve cells have a very complex structure, with elongated projections that can reach up to a meter and extend to all tissues in the body, understanding their function requires the study of their different morphological parts independently. In fact, the very endings of these nerve cell have the capacity produce proteins according to their functional needs. We have used modern approaches in tissue culture and sequencing to identify some potential targets (mRNA) that might be locally synthetised in the nerve endings to produce proteins involved in sensitization. This project aims to test them to see if they really do play a role and unravel their molecular mechanisms. To do this, we are using a simple model system - fruit flies.Although fruit flies might seem very different to mammals like us, their nerves cell are very similar to human nerves in structure and function- they use similar molecular mechanisms and display many key pain signalling proteins in common to those in humans. Drosophila has been proven as a valid model to study many processes including pain sensation ( nociception) and sensitisation. Drosophila larvae respond to pain by rolling away from the noxious stimulus, and this behaviour is modulated by inflammation. Moreover the Drosophila equivalent of our skin is transparent so we can mark and visualise our protein of interest. In this project we will use established and state-of-the-art tools to visualise nerve cell responses to painful stimuli and investigate the role of our identified targets in sensitization. We have established a behavioural assay to study the effects of the novel targets on the fly larvae's rolling behaviour. We can compare how the larvae react to pain in the presence and absence of the target modulators to identify their role in sensitisation. This will help us identify new proteins involved in sensitization.Additionally, starting from the target with a known role in sensitisation and continuing with the one that we will discover, we will study how they work and how they affect the cells. We will then test our findings in mammalian cells to confirm their effectiveness.What we learn will help us understand how sensory nerves behave under normal and altered circumstances (sensitisation), and allow the design of new medicines to stop chronic pain form happening. By working directly on peripheral sensory nerves - that lie outside the brain - better pain-relieving drugs (analgesics) could be created that lack the addictive and psychoactive effects of centrally-acting agents.

我们的身体对疼痛有一种自然的反应，这有助于我们避免有害的东西。当我们触摸到尖锐的东西时，我们会感到疼痛，并迅速将手移开。这是因为我们身体中的特殊神经细胞检测到疼痛事件，并向我们的大脑发送信息，使我们感到疼痛。疼痛是一种令人不快的感觉，但它很重要，因为它告诉我们有什么不对劲，我们需要采取行动来保护自己。当我们受伤时，比如割伤或瘀伤，我们的身体会向该区域输送额外的血液以帮助愈合。这可能会导致该地区变得肿胀和疼痛，即使我们已经删除了造成伤害的实体。这被称为敏化，这是我们身体在愈合过程中保护受伤部位的自然方式。然而，即使在伤口愈合后，敏感化有时也会持续很长时间，导致适应不良反应和慢性疼痛。我们并不完全了解我们的身体如何协调敏感化，或者是什么使敏感化持续更长时间，但我们知道有许多不同的蛋白质参与其中。其中一些蛋白质可以使我们体内的神经细胞对疼痛更敏感。我们希望了解这些蛋白质是如何工作的，以及它们在神经细胞中的位置，这样我们就可以找到阻止慢性疼痛发生的方法。神经细胞具有非常复杂的结构，具有细长的突起，可以达到一米并延伸到身体的所有组织，了解它们的功能需要独立地研究它们的不同形态部分。事实上，这些神经细胞的末端有能力根据其功能需求产生蛋白质。我们已经使用组织培养和测序的现代方法来鉴定一些可能在神经末梢中局部合成以产生参与致敏的蛋白质的潜在靶标（mRNA）。该项目旨在测试它们，看看它们是否真的发挥作用，并解开它们的分子机制。为了做到这一点，我们使用了一个简单的模型系统-果蝇。虽然果蝇看起来与我们这样的哺乳动物非常不同，但它们的神经细胞在结构和功能上与人类神经非常相似-它们使用类似的分子机制，并显示出许多与人类相同的关键疼痛信号蛋白。果蝇已被证明是一个有效的模型来研究许多过程，包括疼痛感觉（伤害感受）和敏化。果蝇幼虫对疼痛的反应是滚动远离有害刺激，这种行为受到炎症的调节。此外，果蝇相当于我们的皮肤是透明的，所以我们可以标记和可视化我们感兴趣的蛋白质。在这个项目中，我们将使用现有的和最先进的工具来可视化神经细胞对疼痛刺激的反应，并研究我们确定的目标在致敏中的作用。我们已经建立了一个行为分析，研究新的目标对蝇幼虫的滚动行为的影响。我们可以比较幼虫在存在和不存在目标调节剂的情况下对疼痛的反应，以确定它们在敏化中的作用。这将有助于我们识别与致敏有关的新蛋白质。此外，我们将从已知的致敏作用靶点开始，并继续研究我们将发现的靶点，研究它们如何工作以及它们如何影响细胞。然后，我们将在哺乳动物细胞中测试我们的发现，以确认它们的有效性。我们所了解的将有助于我们了解感觉神经在正常和改变的情况下（敏化）的行为，并允许设计新的药物来阻止慢性疼痛的发生。通过直接作用于位于大脑外部的外周感觉神经，可以创造出更好的止痛药物（镇痛药），而这些药物缺乏中枢作用药物的成瘾性和精神活性。