Using human IPSC derived nociceptors as a cellular model to investigate and therapeutically target Nav1.7

慢性疼痛是一个主要的健康问题，影响着五分之一的普通人口，不幸的是，目前的治疗方法不够充分。这是因为它们只对少数患者有效，而且它们也与副作用有关。此外，大量测试治疗疼痛的新药的临床试验都失败了，尽管这些药物在动物模型中显示了令人鼓舞的结果。这在一定程度上可能是由于人类和啮齿动物物种之间这些药物靶标的一些结构和功能的差异。因此，我们需要更多地了解人类疼痛处理的基本生物学，并找到在人类细胞模型中测试新药的中间步骤。我们将使用人类诱导多能干细胞(IPSCs)，这是从健康志愿者(在某些情况下是患者)中提取的细胞，并进行了重新编程，以便在实验室中生长。然后我们可以使用这些细胞来生成人类伤害性感受器。伤害性感受器是感觉组织损伤引起痛感的感觉神经元。我们将使用这些细胞来研究和测试针对离子通道Nav1.7的药物，这是开发治疗疼痛新药的重要靶点。离子通道对调节神经元的兴奋性很重要，特别是这个通道是一个关键的药物靶点，因为来自啮齿动物的数据表明，它是产生伤害性感受器电信号所必需的。Nav1.7在感觉神经元中显示了选择性的表达(因此，以这种离子通道为靶点应该可以避免对身体其他区域的副作用，如心脏和大脑)。最后，编码这种离子通道的基因突变的患者天生就无法感知疼痛。我们将使用基因技术，这样我们就可以制造出人类Nav1.7的“标记”版本，以确定这种蛋白质是如何被贩运到人类伤害性感受器的不同专门区域的。我们还将确定哪些其他蛋白质可以与hNav1.7结合，以及这些蛋白质是否可能调节其功能或改变其运输。我们将确定针对hNav1.7的新药是否可以改变人类伤害性感受器的兴奋性，以及这是否通过对hNav1.7的影响而介导。最终，我们希望更多地了解Nav1.7及其相互作用因子在调节人类伤害性感受器兴奋性方面的基础作用，并验证人iPSC来源的伤害性感受器作为药物发现平台的有效性。

Chronic pain is a major health problem affecting 1 in 5 of the general population and unfortunately current treatments are inadequate. This is because they only work in a minority of patients and they are also associated with side effects. Moreover, a significant number of clinical trials testing new drugs to treat pain have failed, despite these drugs showing encouraging results in animal models. This may partly be due to differences in the structure and function of some of these drug targets between human and rodent species. We therefore need to understand more about the fundamental biology of pain processing in humans and find intermediate steps to test new drugs in a human cellular model. We will use human induced pluripotent stem cells (iPSCs) which are cells that have been taken from healthy volunteers (and in some cases patients) and reprogrammed so that they can be grown in the laboratory We can then use these cells to generate human nociceptors. Nociceptors are the sensory neurons which sense tissue injury giving rise to the sensation of pain. We will use these cells to investigate the role of and test drugs targeting the ion channel Nav1.7, which is an important target for developing new drugs to treat pain. Ion channels are important for regulating the excitability of neurons and this channel in particular is a key drug target because data from rodents suggest that it is needed for the generation of electrical signals in nociceptors. Nav1.7 shows selective expression within sensory neurons (so targeting this ion channel should avoid side effects in other regions of the body such as the heart and brain). Finally, patients with mutations in the gene encoding this ion channel are born unable to perceive pain. We will use gene technology so that we can produce a 'tagged' version of human Nav1.7 in order to determine how this protein is trafficked to the different specialised regions of human nociceptors. We will also determine which other proteins can bind to hNav1.7 and whether these proteins may modulate its function or alter its trafficking. We will determine whether the new drugs being developed to target hNav1.7 can alter the excitability of human nociceptors and whether this is mediated through effects on hNav1.7. Ultimately, we hope to learn more about the fundamental role of Nav1.7 and its interactors in regulating the excitability of human nociceptors and validate human iPSC derived nociceptors as a platform for drug discovery.