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

点击翻译按钮获取中文摘要

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.