MICA: Exploiting specialised pro-resolution molecule mediated analgesia to identify novel targets for the treatment of chronic pain

骨关节炎（OA）和糖尿病性神经病变通常与慢性疼痛有关，正如我们的PPIE代表所强调的那样，这对日常生活产生了巨大的影响。并非所有患有这些疾病的人都会经历慢性疼痛，了解这些差异可能会为新的治疗方法提供见解。由身体产生的一系列天然分子（专门的前分辨率分子（SPM））在疼痛的动物模型中具有强大的镇痛作用，而SPM水平较低的健康志愿者对疼痛更敏感。至关重要的是，我们发现，SPM水平较低的OA患者会经历更多的疼痛。SPM通过干扰多个信号通路来减轻疼痛，从而产生强烈的镇痛作用。尽管SPM很快被分解成无活性的产物，但它们具有持久的影响-这一过程可能是由于已知在基因表达水平上驱动疼痛反应的分子的调节。我们已经确定了基因通路牵连的SPM对OA pain in people.Aim的影响：要确定的细胞和分子过程，导致强大的和持久的镇痛所产生的SPM，并利用这些信息，以确定新的治疗方法，以改善慢性疼痛的治疗。队伍：这项新研究由我们的PPIE指导小组指导，并由一个团队领导，该团队为慢性疼痛机制，疼痛遗传学和实验性疼痛带来了力量。制药公司Eli Lilly带来了分析和整合大规模数据集的专业知识，以最大限度地发挥这些有价值的临床数据集的优势。实验计划：我们将使用内部生物信息学方法来分析我们现有的和新获得的数据，以预测特定的分子（称为microRNA），这些分子可能调节与高水平和低水平SPM相关的基因表达变化及其与慢性疼痛的关系。首先，我们将收集OA疼痛患者（和对照非OA组）的血液，对预测调节与OA疼痛相关的基因水平和特定稳定分子水平的microRNA进行详细分析，该分子是许多SPM的前体，称为17-HDHA。使用现有的计算工具，我们将确定与17-HDHA水平高低相关的microRNA，以及这与OA疼痛的关系。我们将在患有不同类型慢性疼痛（伴有和不伴有疼痛的糖尿病神经性疼痛）的患者中验证这些发现，以确定这两种类型慢性疼痛之间的共性和差异，从而确定特定于疾病的靶标，以及它们之间共享的靶标。为了关注这些途径在驱动疼痛中的潜在作用，对来自关节组织和已经从OA患者（由我们的合作者）收集的滑液的现有microRNA数据集进行计算分析，将确定我们已经确定的哪些microRNA也存在于疾病部位和疼痛来源。使用实验模型和工具，我们将确定哪些临床鉴定的microRNA被小鼠中的17-HDHA治疗改变，支持哪些途径可能是新疗法的候选者。专门开发来操纵这些microRNA功能的分子工具将用于鉴定介导17-HDHA对驱动疼痛反应的兴奋性感觉神经活动的影响的miRNA。这种方法将优先考虑临床鉴定的microRNA，以最有可能用于慢性OA疼痛患者的治疗开发。这一结果的重要性得到了我们的PPIE代表的支持，因为患有疼痛的人希望开发新的治疗方法，以减轻他们现有的疼痛，并使他们拥有更充实，更快乐的生活体验。

Osteoarthritis (OA) and diabetic neuropathy are often associated with chronic pain which, as highlighted by our PPIE representatives, hugely impacts upon daily life. Not everybody with these diseases experiences chronic pain, and understanding these differences may offer insight into new treatments. A family of natural molecules produced by the body (specialised pro-resolution molecules (SPMs)) have robust analgesic effects in animal models of pain, while healthy volunteers with lower levels of SPMs are more sensitive to pain. Crucially, we showed that people with OA who have lower levels of SPMs experience significantly more pain. The SPMs reduce pain by interfering with multiple signalling pathways, leading to strong analgesic effects. Although SPMs are quickly broken-down into inactive products, they have long-lasting effects - a process likely to be due to the modulation of molecules known to drive pain responses at the gene expression level. We have already identified gene pathways implicated in the effects of the SPMs on OA pain in people.Aim: To identify the cellular and molecular processes that lead to the powerful and long-lasting analgesia produced by the SPMs and to use this information to identify new therapeutic approaches to improve the treatment of chronic pain. Team: This new research is guided by our PPIE steering group, and is lead by a team which brings strength in chronic pain mechanisms, genetics of pain and experimental pain. The pharmaceutical company Eli Lilly brings expertise in analysing and integrating large-scale datasets to maximise the benefits of these valuable clinical datasets. The project also supports the career development of researcher co-investigator Dr P Gowler.Experimental Plan: We will use in-house bioinformatic approaches to analyse our existing and newly acquired data to predict the specific molecules (known as microRNAs) which may regulate changes in gene expression associated with high versus low levels of SPMs and their relationships with chronic pain. First we will collect blood from people with OA pain (and control non-OA group) to undertake a detailed analysis of microRNAs that are predicted to regulate the levels of genes associated with OA pain and levels of a specific stable molecule which is a precursor for many SPMs, known as 17-HDHA. Using existing computational tools we will identify the microRNAs associated with having high versus low levels of 17-HDHA and how this relates to the OA pain experienced. We will validate these findings in patients with a different type of chronic pain (diabetic neuropathic pain with and without pain) to identify commonality and differences between these two types of chronic pain, thus identifying targets that are specific to the diseases, and those shared between them. To focus on potential roles of these pathways in driving pain, computational analysis of existing microRNA datasets from joint tissue and synovial fluid already collected from people with OA (by our collaborator) will identify which microRNAs that we have identified are also present at the site of disease and the source of the pain. Using experimental models and tools we will identify which of the clinically identified microRNAs are altered by 17-HDHA treatment in mice, supporting which pathways are likely candidates for novel therapeutics. Molecular tools specifically developed to manipulate the function of those microRNAs will be used to identify the miRNAs that mediate the effects of the 17-HDHA on excitatory sensory nerve activity that drives pain responses. This approach will prioritise the clinically identified microRNAs to those with the most potential for therapeutic development for people with chronic OA pain. The importance of this outcome was supported by our PPIE representatives, as people living with pain want the development of new treatments which reduce their existing pain and allows them to have a fuller and happier life experience.