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MICA: A comprehensive genomic and functional approach to discover new ion channel targets for human pain treatment

MICA：一种全面的基因组和功能方法，用于发现人类疼痛治疗的新离子通道靶标

基本信息

批准号：
MR/J012742/1
负责人：
Geoff Woods
金额：
$ 127.25万
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FJ012742%2F1
关键词：
MICA comprehensive genomic functional approach

项目摘要

Pain is common, affecting 1 in 6 adults. Pain is also often complex; the sudden pain of a cut, burn or fractured bone (nociceptive pain), or the longer term aching pain associated with cancer or chronic injuries (neuropathic pain) or, more commonly, a mixture of both types. It is currently impossible to tell how much pain a person is suffering or to compare this pain accurately between people. Furthermore it can be difficult to determine the origin of pain, and we know that once pain has started it can become self-perpetuating probably due to secondary changes in the spinal cord or brain. We also all have experienced the depression and debilitation pain can cause if it is either severe or long lasting. Finally, pain treatment if often successful for mild pain and short lived nociceptive pain; however treatments for chronic pain are far less effective and often lead to side effects.We, and others, have previously shown that some members of a class of genes called ion channels are essential to produce pain. Ion channel genes code for proteins that sit on the surface of neurons and either detect pain and turn this into a voltage signal, or respond to other proteins that detect pain and amplify their signal. We found that an ion channel gene called SCN9A can control all nociceptive pain felt (causing a condition called Congenital Insensitivity to Pain in people with no working SCN9A gene) and that another ion channel gene HCN2 controls neuropathic pain (this time in mice studies, where the mice with no HCN2 gene did not feel any neuropathic pain). In both people with no SCN9A and mice with no HCN2 the lack of pain sensing was the only feature. This is very important and suggests that if you could design a drug to block SCN9A and/or HCN2 you would have a new type of analgesic without side effects.We now want to look for further ion channels that are part of the mechanism that make people feel pain. We are taking a novel approach by using three groups of people who feel extremes of pain: one group are people with severe neuropathic pain who get referred to a specialized pain clinic in Cambridge after other approaches have failed. These people have multiple reasons why they first experienced pain but are distinguished by their persistent pain becoming more severe and stopping them working and functioning normally. This group is currently extremely difficult to treat and is a significant problem for our society and the NHS. Our second group consists of women who don't need pain relief during their first delivery - constituting only 1% of women in the Rosie Maternity Hospital in Cambridge. We don't know whether these women are stoical, just determined not to have any drugs, have a quick labour, or have a very high pain threshold (probably a mix), but most importantly some of these women have other family members who similarly didn't need analgesia during their first labour strongly suggesting that this may be a genetic trait. Our third group if of very rare families with extremes of pain sensing - either feeling no pain or very early onset of severe debilitating pain. It is from researching this group that we found SCN9A.We will select the 300 people from these three cohorts with the most severe pain findings and sequence all of their ion channel genes. What we are looking for is changes in ion channel genes that will change the way they work. If we find an ion channel gene change in a patient, say with severe neuropathic pain, and then find that in the laboratory that the mutation alters the way the ion channel works, then that ion channel could be important for pain control in humans with neuropathic pain. We will need to perform further studies on each gene we identify to provide further proof of its role in pain. Each ion channel we identify has the potential to generate new analgesics leading to better pain control for our patients.

疼痛很常见，影响六分之一的成年人。疼痛通常也很复杂；割伤、烧伤或骨折的突然疼痛（伤害性疼痛），或与癌症或慢性损伤相关的长期疼痛（神经性疼痛），或更常见的是两种类型的混合。目前无法判断一个人正在承受多少痛苦，也无法在人与人之间准确地比较这种痛苦。此外，确定疼痛的根源可能很困难，而且我们知道，一旦疼痛开始，它可能会由于脊髓或大脑的继发性变化而自我持续。我们也都经历过严重或长期持续的抑郁和虚弱疼痛。最后，如果疼痛治疗经常成功缓解轻度疼痛和短暂的伤害性疼痛；然而，慢性疼痛的治疗方法远不那么有效，而且常常会导致副作用。我们和其他人之前已经证明，离子通道基因的某些成员对于产生疼痛至关重要。离子通道基因编码位于神经元表面的蛋白质，这些蛋白质要么检测疼痛并将其转化为电压信号，要么对检测疼痛并放大其信号的其他蛋白质做出反应。我们发现，一种名为 SCN9A 的离子通道基因可以控制所有伤害性疼痛（在没有工作的 SCN9A 基因的人中导致一种称为先天性疼痛不敏感的病症），而另一种离子通道基因 HCN2 控制神经性疼痛（这次在小鼠研究中，没有 HCN2 基因的小鼠没有感觉到任何神经性疼痛）。在没有 SCN9A 的人和没有 HCN2 的小鼠中，缺乏疼痛感是唯一的特征。这非常重要，表明如果你能设计一种药物来阻断 SCN9A 和/或 HCN2，你就会得到一种没有副作用的新型镇痛药。我们现在想要寻找更多的离子通道，它们是让人感到疼痛的机制的一部分。我们正在采取一种新颖的方法，使用三组感到极度疼痛的人：一组是患有严重神经性疼痛的人，在其他方法失败后被转诊到剑桥的专门疼痛诊所。这些人第一次经历疼痛的原因有多种，但其特点是持续疼痛变得更加严重，并导致他们无法正常工作和功能。该群体目前极难治疗，对我们的社会和 NHS 来说是一个重大问题。我们的第二组由第一次分娩时不需要缓解疼痛的女性组成，仅占剑桥 Rosie 妇产医院女性的 1%。我们不知道这些女性是否坚忍，只是决定不使用任何药物，快速分娩，或者具有非常高的疼痛阈值（可能是混合），但最重要的是，其中一些女性的其他家庭成员在第一次分娩时同样不需要镇痛，强烈表明这可能是一种遗传特征。我们的第三组是非常罕见的具有极端疼痛感觉的家庭——要么感觉不到疼痛，要么很早就出现严重的使人衰弱的疼痛。正是通过对这个群体的研究，我们发现了 SCN9A。我们将从这三个群体中选择疼痛最严重的 300 人，并对他们所有的离子通道基因进行测序。我们正在寻找的是离子通道基因的变化，这将改变它们的工作方式。如果我们在患有严重神经性疼痛的患者中发现离子通道基因发生变化，然后在实验室中发现该突变改变了离子通道的工作方式，那么该离子通道对于患有神经性疼痛的人类的疼痛控制可能很重要。我们需要对我们识别的每个基因进行进一步的研究，以进一步证明其在疼痛中的作用。我们发现的每个离子通道都有可能产生新的镇痛药，从而更好地控制患者的疼痛。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Transcriptional regulator PRDM12 is essential for human pain perception.

DOI：
10.1038/ng.3308
发表时间：
2015-07
期刊：
Nature genetics
影响因子：
30.8
作者：
Chen YC;Auer-Grumbach M;Matsukawa S;Zitzelsberger M;Themistocleous AC;Strom TM;Samara C;Moore AW;Cho LT;Young GT;Weiss C;Schabhüttl M;Stucka R;Schmid AB;Parman Y;Graul-Neumann L;Heinritz W;Passarge E;Watson RM;Hertz JM;Moog U;Baumgartner M;Valente EM;Pereira D;Restrepo CM;Katona I;Dusl M;Stendel C;Wieland T;Stafford F;Reimann F;von Au K;Finke C;Willems PJ;Nahorski MS;Shaikh SS;Carvalho OP;Nicholas AK;Karbani G;McAleer MA;Cilio MR;McHugh JC;Murphy SM;Irvine AD;Jensen UB;Windhager R;Weis J;Bergmann C;Rautenstrauss B;Baets J;De Jonghe P;Reilly MM;Kropatsch R;Kurth I;Chrast R;Michiue T;Bennett DL;Woods CG;Senderek J
通讯作者：
Senderek J

Clathrin heavy chain 22 contributes to the control of neuropeptide degradation and secretion during neuronal development.

网格蛋白重链 22 有助于控制神经元发育过程中的神经肽降解和分泌。