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自然的反应，这有助于我们避免有害的事情。当我们碰到尖锐的东西时，我们会感到痛苦，并迅速将手移开。这是因为我们体内的特殊神经细胞检测到痛苦的事件，并向我们的大脑发送信息，使我们感到疼痛。疼痛是一种令人不愉快的感觉，但这很重要，因为它告诉我们有些问题，我们需要采取行动来保护自己。当我们受伤时，例如割伤或瘀伤，我们的身体会向该地区提供额外的血液来帮助其治愈。即使我们去除了造成伤害的实体，这也可能导致该地区肿胀和痛苦。这称为敏化，这是我们身体在治愈时保护受伤区域的自然方法。但是，即使受伤愈合，有时甚至可以持续很长时间，导致不良适应性反应和慢性疼痛。我们不完全了解我们的身体如何协调敏感，或者是什么使敏化持续更长的时间，但我们确实知道涉及许多不同的蛋白质。这些蛋白质中的一些可以使我们体内的神经细胞对疼痛更敏感。我们想了解这些蛋白质如何工作以及它们位于神经细胞中的位置，以便我们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，细长的投影可以达到仪表高达一米，并扩展到体内的所有组织，了解它们的功能需要独立地研究其不同的形态学部分。实际上，这些神经细胞的结局具有根据其功能需求产生蛋白质的能力。我们已经使用了组织培养和测序中的现代方法来识别一些可能在神经末梢局部合成的潜在靶标（mRNA），以产生参与敏化的蛋白质。该项目旨在测试他们，以查看它们是否确实发挥作用并揭示其分子机制。为此，我们使用了一个简单的模型系统 - 果蝇。尽管果蝇似乎与像我们这样的哺乳动物似乎有很大不同，但它们的神经细胞与结构和功能中的人类神经非常相似 - 他们使用相似的分子机制，并显示出许多与人类中常见的关键疼痛信号蛋白。果蝇已被证明是研究许多过程，包括疼痛感觉（伤害感受）和敏化。果蝇幼虫通过摆脱有害刺激来应对疼痛，这种行为受炎症调节。此外，果蝇等效于我们的皮肤是透明的，因此我们可以标记和可视化感兴趣的蛋白质。在这个项目中，我们将使用已建立的最先进的工具来可视化神经细胞对疼痛刺激的反应，并研究我们确定的靶标在敏化中的作用。我们已经建立了一种行为测定，以研究新靶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，以识别其在致敏性中的作用。这将有助于我们确定参与敏化的新蛋白质。从目标开始，从靶标开始，在致敏中起着已知的作用，并继续与我们发现的蛋白质保持联系，我们将研究它们的工作原理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，以确认其有效性。我们学到的知识将帮助我们了解感觉神经在正常和改变情况下的行为如何（致敏），并允许新药物的设计停止发生慢性疼痛形式。通过直接在大脑外部的外围感觉神经上工作 - 可以创建更好的疼痛药物（镇痛药），这些药物缺乏中心作用剂的成瘾性和精神活性作用。