Integrative Modulation of Trafficking and Signaling of TRPA1 Channels for Sustained pain

慢性和长期疼痛是最常见的健康问题之一。它也是许多全身性疾病如糖尿病、癌症和心脏病最常见的并发症之一。据估计，在英国，慢性疼痛影响着2800万人（43%），老年人的发病率甚至更高。慢性疼痛对患者的生活质量和日常活动产生不利影响，甚至导致残疾和缺勤。此外，这给他们的家庭带来了巨大的压力。慢性疼痛的成本是巨大的，估计每年在5-10亿英镑之间。因此，慢性疼痛造成了重大的社会和经济负担。然而，目前的治疗方法要么缺乏疗效，要么产生难以忍受的副作用。因此，为了设计预防和治疗慢性疼痛的新方法，有相当大的需要了解慢性疼痛是如何产生和维持的。对疼痛的感知始于感觉神经末梢上的痛觉蛋白受到来自环境或身体的有害刺激的激活。一旦被激活，这些痛觉蛋白就会触发痛觉电信号，然后这些电信号被传送到脊髓和大脑，在那里痛觉信号被解读。一种名为TRPA1的痛觉蛋白尤为重要。TRPA1被各种各样的有害刺激激活，就像一个通用的疼痛传感器，将有害信息转化为疼痛信号。重要的是，trpa1诱导的疼痛比其他痛觉蛋白引起的疼痛更严重、更持久。因此，TRPA1与许多不同类型的慢性疼痛有关，从炎症性疼痛、神经性疼痛、偏头痛和关节炎疼痛到糖尿病疼痛，这并不奇怪。然而，人们对TRPA1是如何导致持续疼痛的知之甚少。在我们的初步研究中，我们在痛觉神经细胞中发现了一种重要的蛋白质。有趣的是，消融该蛋白完全消除了TRPA1携带的持久疼痛，表明该蛋白在持续疼痛中起着至关重要的作用。在这项研究中，我们的目标是进一步了解这种蛋白质如何与TRPA1一起作用，从而对持续疼痛产生如此巨大的影响。具体来说，我们想知道该蛋白在正常和疾病条件下如何影响TRPA1的功能，以及它如何促进疼痛信使和疼痛转导的激活。最后，我们将研究这种蛋白是否也对疼痛致敏和持久炎症性疼痛至关重要。综上所述，这项研究将揭示神经细胞中一种以前未被识别的蛋白质在调节TRPA1和控制慢性疼痛中的新作用，并揭示其工作原理。这将极大地促进我们对慢性疼痛是如何产生和维持的理解。这种蛋白质对持续疼痛的巨大作用表明，这种蛋白质在开发治疗慢性疼痛的新治疗靶点方面具有巨大的潜力。如果是这样的话，这项研究将使数百万被当前疼痛疗法治疗不足的患者受益。

Chronic and prolonged pain is one of the most frequent health problems. It is also one of the most common complications to many systemic diseases such as diabetes, cancer and heart diseases. It is estimated that chronic pain affects 28 million people in the UK (43%) and the incidence is even higher in the elderly. Chronic pain has a detrimental impact on quality of life and daily activities of the patients, and even causes disability and absence from work. Furthermore, it causes substantial stress on their families. The cost of chronic pain is huge estimated to be between £5-10 billion per year. Chronic pain thus poses a significant societal and economic burden. However, the current treatments either lack efficacy or produce intolerable side effects. Therefore, there is a considerable need to understand how chronic pain is generated and maintained in order to devise new approaches for the prevention and treatment of chronic pain. The perception of pain begins with activation of pain-sensing proteins on sensory nerve endings by harmful stimuli either from the environment or from the body. Once activated, these pain sensing proteins trigger electrical pain signals, which are then transmitted to the spinal cord and brain where pain signals are interpreted. A pain-sensing protein called TRPA1 is of particular importance. TRPA1 is activated by a vast variety of harmful stimuli acting like a universal pain sensor serving to translating harmful information into pain signals. Importantly, TRPA1-induced pain is more severe and long-lasting than that caused by other pain-sensing proteins. It is therefore not surprising that TRPA1 has been implicated in many different types of chronic pain ranging from inflammatory pain, neuropathic pain, migraine and arthritis pain to diabetic pain. However, it remains poorly understood how TRPA1 is predisposed to drive sustained pain. In our pilot studies, we have identified an important protein in pain sensing nerve cells. Interestingly, ablation of this protein entirely eliminated long-lasting pain carried by TRPA1, suggesting a crucial role for this protein in sustained pain. In this research, we aim to further understand how this protein works with TRPA1 to achieve such a dramatic effect on sustained pain. Specifically, we would like to know how this protein influences the function of TRPA1 under normal and disease conditions, and how it promotes activation of pain messengers and pain transduction. Finally, we will study whether this protein is also critical to pain sensitization and long-lasting inflammatory pain. Taken together, this research will reveal the novel role of a previously unrecognized protein in nerve cells in the regulation of TRPA1 and governing chronic pain, and uncover how it works. It will significantly advance our understanding how chronic pain is generated and maintained. The dramatic effect of this protein on sustained pain suggests a huge potential for this protein to be harnessed for developing novel therapeutic targets for the treatment of chronic pain. If this is the case, this research will benefit the millions of patients who are under-treated by the current pain therapies.