Unravelling dorsal root ganglion as an intrinsic filtering device

病理性疼痛继续构成一个巨大但尚未解决的健康问题。尽管进行了几个世纪的研究和投资，但对许多病理性疼痛状况的精确机制理解仍然不完整，阿片类药物(如吗啡)仍然是止痛的黄金标准。因此，许多类型的疼痛(如慢性关节炎疼痛、偏头痛、神经病理性疼痛和癌症疼痛)尤其难以治疗，因为大多数传统止痛药要么不能缓解这些疼痛，要么有严重的副作用。为了感知和评估我们的环境，人类配备了外周神经(外周体感系统)。这些神经贯穿我们的身体，收集关于周围环境的僵硬、温度和化学成分的信息，也收集关于我们自身身体完整性的信息。特定的“损伤感知”神经(伤害性感受器)负责产生痛感。为了理解和治疗疼痛，我们需要更好地理解伤害性神经纤维如何将信号从外周传导到形成痛觉的中枢神经系统(CNS)的机制。我们发现，每条神经中都有一种结构，可以限制向中枢神经系统传递多少“疼痛”信号。这些微观的“过滤器”可能掌握着我们阻止这些信号到达大脑的能力的关键。这个项目的重点是破译这些“信号过滤器”是如何工作的，最终目标是利用这些过滤器提供新的方法，在一系列令人虚弱的条件下减轻疼痛。我们的初步工作证实，这种过滤在专门处理疼痛的神经中是强大的，但在其他感觉神经中就不那么强大了。然而，关于这些过滤器如何工作的总体原理，为什么它们在不同类型的神经中不同地工作，或者这种过滤器在慢性疼痛条件下如何变化，几乎什么都不知道。我们的项目试图通过三个具体的目标来回答这些有趣的问题：i)获得关于不同类型感觉神经中这些过滤器的设计的详细信息。Ii)为不同神经的过滤过程创建生物逼真的计算机模型。Iii)测试由于神经损伤导致的慢性疼痛的临床前模型中这种过滤是如何改变的。为了实现上述目标，我们开发了一种综合的多学科方法，结合了尖端生物学方法，例如所谓的光片显微镜，允许深入观察动物组织、体内研究和广泛的计算机建模。我们相信，这项研究将带来对人类感觉系统的新理解，特别是对慢性疼痛机制的理解。重要的是，我们的发现可能会形成止痛药开发和有效疼痛管理的新方法，从而对患有慢性疼痛的个人有显著的好处。

Pathological pain continues to constitute an enormous yet unresolved health problem. Despite centuries of research and investment, the precise mechanistic understanding of numerous pathological pain conditions remains incomplete and opioids (such as morphine) are still a 'gold standard' in analgesia. Accordingly, many types of pain (such as chronic arthritis pain, migraine, neuropathic and cancer pains) are particularly difficult to treat since most of the conventional pain-killers either do not relieve such pain or have serious side-effects.In order to perceive and evaluate our environment, humans are equipped with peripheral nerves (peripheral somatosensory system). These nerves run through our body and collect information about rigidity, warmth and chemical composition of the surrounding milieu and also about our own body's integrity. Specific 'damage-sensing' nerves (nociceptors) are responsible for generating pain sensation. In order to understand and treat pain we need a better understanding of the mechanisms of how nociceptive nerve fibers conduct signals from the periphery to the central nervous system (CNS) where the perception of pain is formed. We have discovered that there is a structure within each nerve that can limit how much of 'pain' signal is delivered to CNS. These microscopic 'filters' may hold a key to our ability to block these signals off so that they do not reach the brain. This project is focused on deciphering how these 'signal filters' work, with an ultimate goal to leveraging these to provide new ways to relieve pain in a range of debilitating conditions. Our preliminary work established that such filtering is robust in nerves that deal with pain specifically but less so in other sensory nerves. However, hardly anything is known about the overall principles of how these filters work, why they work differently in nerves of different type or how this filtering changes in chronic pain conditions. Our project attempts to answer these intriguing questions through three specific aims:i) Obtain detailed information on the design of these filters in sensory nerves of different types. ii) Create biologically realistic computer models for the filtering process in different nerves. iii) Test how such filtering is altered in preclinical models of chronic pain due to nerve injury.To achieve the above aims we have developed a comprehensive and multidisciplinary approach which combines cutting-edge biology approaches, such as what is called light-sheet microscopy allowing to look deep into animal tissue, in vivo studies and extensive computer modelling. We are confident that this research will bring new understanding of human sensory systems and, particularly, of chronic pain mechanisms. Importantly, our findings may shape new approaches for analgesic drug development and effective pain management, thus having significant benefit for individuals who suffer from chronic pain conditions