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

MICA：利用专门的促消退分子介导的镇痛来确定治疗慢性疼痛的新靶点

• 批准号: MR/W02652X/1
• 负责人: Victoria Chapman
• 金额: $ 81.14万
• 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: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW02652X%2F1
• 关键词: MICA; Exploiting; specialised; pro; resolution

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.

骨性关节炎(OA)和糖尿病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，这种疼痛对日常生活产生了巨大影响。并不是每个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洞察力。在疼痛的动物模型中，一系列由人体产生的天然分子(特殊的促分解分子(SPM))具有强大的止痛效果，而SPM水平较低的健康志愿者对疼痛更敏感。最重要的是，我们发现患有骨性关节炎的患者在SPM水平较低时会体验到明显更多的疼痛。SPM通过干扰多个信号通路来减轻疼痛，从而产生强烈的止痛作用。尽管SPM很快就会分解成不活跃的产物，但它们具有长期的影响-这一过程很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SPM对人的骨性关节炎疼痛的影响所涉及的基因通路。目的：确定导致SPM产生强大而持久的止痛的细胞和分子过程，并利用这些信息来确定新的治疗方法，以改善慢性疼痛的治疗。团队：这项新的研究由我们的PPIE指导小组指导，并由一个在慢性疼痛机制、疼痛遗传学和实验性疼痛方面带来力量的团队领导。制药公司礼来公司带来了分析和集成大规模数据集的专业知识，以最大限度地发挥这些宝贵的临床数据集的好处。该项目还支持研究人员合作者P·高勒博士的职业发展。实验计划：我们将使用内部生物信息学方法分析现有和新获得的数据，以预测特定分子(称为microRNAs)，这些分子可能调节与高水平和低水平的SPM相关的基因表达的变化，以及它们与慢性疼痛的关系。首先，我们将收集骨性关节炎疼痛患者(和非骨性关节炎患者组)的血液，对microRNAs进行详细分析，这些microRNAs被预测为调节与骨性关节炎疼痛相关的基因水平，以及一种特定的稳定分子的水平，该分子是许多SPM的前体，称为17-HDHA。使用现有的计算工具，我们将确定与高水平和低水平的17-HDHA相关的microRNA，以及这与所经历的OA疼痛的关系。我们将在不同类型的慢性疼痛(有无疼痛的糖尿病神经性疼痛)患者中验证这些发现，以确定这两种类型的慢性疼痛之间的共同点和差异，从而确定特定于疾病的靶点，以及它们之间共享的靶点。为了关注这些通路在驱动疼痛中的潜在作用，对(我们的合作者)已经从OA患者那里收集的关节组织和滑液的现有microRNA数据集进行计算分析，将确定我们已经确定的哪些microRNA也存在于疾病的部位和疼痛的来源。使用实验模型和工具，我们将确定哪些临床识别的microRNAs在小鼠身上被17-HDHA治疗改变，支持哪些途径可能是新疗法的候选者。为操纵这些microRNAs的功能而专门开发的分子工具将被用来识别介导17-HDHA对兴奋性感觉神经活动的影响的miRNAs，从而驱动疼痛反应。这一方法将把临床确定的microRNA优先用于那些最有潜力为慢性骨性关节炎疼痛患者开发治疗的微RNA。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，以减少他们现有的疼痛，并使他们拥有更充分和更快乐的生活体验。