Development of Purine-based novel analgesics

项目概述：这个mrc资助的博士培训合作伙伴关系（DTP）将尖端的分子和分析科学与数据分析中的创新计算方法结合起来，使学生能够在与行业一致的优先领域解决重要的应用生物医学研究问题。这是一个为期4年的课程，第一年包括一系列教学模块和两个基于实验室的研究项目，最终获得跨学科生物医学研究硕士学位。前两个学期包括一系列教学模块，让学生在多学科科学方面打下坚实的基础。学生还将参加一系列由分子、细胞和组织动力学、微生物学和感染、应用生物医学技术、人工智能和数据科学等领域的学术和行业专家主持的大师班。在第三学期和夏季学期，学生在他们选择的实验室进行两个为期11周的研究项目。项目概述：慢性疼痛是一种使人衰弱的疾病，对患者、其家庭和整个社会造成严重影响，造成保健费用和因健康不佳而损失的天数和生产力。虽然有许多可用的止痛药，但一些疼痛患者并没有从疼痛缓解中受益，并且/或者遭受不可接受的不良反应。以阿片类药物为基础的止痛药尤其如此，依赖、成瘾、滥用和死亡的风险导致了所谓的“阿片类药物危机”，并导致美国和其他地方数万人死亡。因此，这些限制生命的疾病的患者需要安全有效地管理疼痛的新疗法。在这个项目中，我们将与NeuroSolutions（一家疼痛和镇痛方面的合同研究组织专家）合作，研究以嘌呤分子为中心的新型化合物，这些化合物会干扰疼痛通路，以探索它们在一系列临床相关疼痛模型中的细胞作用和治疗潜力。重要的是，这些化合物是基于我们发现的一种分子，它具有非常不寻常的特性，有可能提供强大的止痛药，但没有先前观察到的针对这种特殊生物过程的分子对心血管和呼吸系统的副作用。该项目将通过我们在瑞士的合作者涉及新的有机合成化学；考文垂和埃塞克斯大学的一个研究小组对药物行为进行了复杂的分子模拟；与剑桥大学的同事一起详细描述了这些药物在简化细胞系统中的作用，并在试管和全动物实验中对这些分子进行了深入的研究，包括神经元通讯、心血管和呼吸生理学、疼痛途径、运动、成瘾潜力和镇静。所有这些研究都将以对这些化合物在生物系统中的作用进行严格的定量评估为基础。通过这项研究的结论，我们期望已经确定的化合物与潜在的临床试验的人。

Programme overview:This MRC-funded doctoral training partnership (DTP) brings together cutting-edge molecular and analytical sciences with innovative computational approaches in data analysis to enable students to address important applied biomedical research questions in priority areas aligned with industry. This is a 4-year programme whose first year involves a series of taught modules and two laboratory-based research projects that lead to an MSc in Interdisciplinary Biomedical Research. The first two terms consist of a selection of taught modules that allow students to gain a solid grounding in multidisciplinary science. Students also attend a series of masterclasses led by academic and industry experts in areas of molecular, cellular and tissue dynamics, microbiology and infection, applied biomedical technologies and artificial intelligence and data science. During the third and summer terms students conduct two eleven-week research projects in labs of their choice. Project overview:Chronic pain is a debilitating condition that has severe implications for the sufferer, their families and society in general in terms of health care costs and days and productivity lost to ill-health.Whilst there are numerous pain medications available, some pain sufferers do not benefit from pain relief and/or suffer unacceptable adverse effects. This is particularly the case for opioid-based painkillers where the risk of dependence, addiction, abuse and death has contributed to what has been termed "the opioid crisis", and which has led to the deaths of tens of thousands of people in the USA and elsewhere. Novel treatments for the safe and effective management of pain are thus required for sufferers of these life-limiting conditions.In this project, in collaboration with NeuroSolutions, a contract research organisation expert in pain and analgesia, we will investigate novel compounds, centred around molecules known as purines, that interfere with pain pathways to explore their cellular actions and therapeutic potential in an range of clinically-relevant models of pain. Importantly, these compounds, based upon a molecule whose highly unusual properties we discovered, have the potential to provide strong pain-killing, but without the cardiovascular and respiratory side effects previously observed with molecules targeting this particular biological process.The project will involve novel organic synthetic chemistry through our collaborator in Switzerland; sophisticated molecular simulations of drug behaviour with a team at Coventry & Essex universities; detailed cellular characterisation of the actions of these drugs in simplified cellular systems with colleagues at Cambridge University, and in-depth examination of these molecules in both test-tube and whole animal assays of neuronal communication, cardiovascular and respiratory physiology, pain pathways, locomotion, addiction potential and sedation. All of these studies will be underpinned by rigorous quantitative assessment of the effects of these compounds in biological systems.By the conclusion of this study we expect to have identified compounds with the potential for clinical trials in man.