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Brain-enriched voltage-gated calcium channel isoforms: novel, genetically informed, therapeutic targets for psychiatric disorders

脑富集电压门控钙通道亚型：精神疾病的新型、遗传信息治疗靶点

基本信息

批准号：
MR/P026028/1
负责人：
Elizabeth Tunbridge
金额：
$ 57.45万
依托单位：
University of Oxford
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FP026028%2F1
关键词：
Brain enriched voltage gated calcium

项目摘要

The last few years have seen substantial progress in our understanding of the genetic basis of psychiatric illnesses such as schizophrenia and bipolar disorder (also known as manic depression). It is hoped, and often claimed, that this knowledge will lead to insights into the biology of these illnesses and new therapies. However, concrete examples of this argument are lacking. This research will begin to examine how we can move from genetic insights to new therapies by focussing on arguably the most promising set of molecules arising from the recent genetic studies: the voltage gated calcium channels (VGCCs).Calcium is an important signalling molecule and plays a key role in brain function. There is long-standing evidence that patients with bipolar disorder have abnormalities in calcium function. Recent genetic studies suggest that these abnormalities may be caused, in part, by alterations in the function of the VGCCs. These channels make attractive drug targets for treating bipolar disorder and other psychiatric disorders in which these channels are implicated. However, many different types of VGCCs are produced from a limited number of VGCC genes, and there is a lack of information about the precise types of VGCCs that are present in human brain, and how these channels are changed in psychiatric disorders and in those at higher genetic risk for these illnesses. Neither do we know how the critical brain VGCCs differ from those found elsewhere in the body. This grant will directly answer these three questions by identifying the VGCCs present and enriched in human brain, compared to other body tissues, and investigating how they are changed in association with genetic risk for psychiatric disorders, and in the diseases themselves. These studies will take advantage of a wealth of data that has already been collected, some of which we have unique access to. We will combine analysis of these existing datasets with cutting-edge experimental studies. Crucially, both our analyses and experiments will use human brain tissue. This is essential, because the number of different molecules that a single gene produces is much higher in humans than in others species, particularly in human brain, compared with other types of body tissue. Most of the studies that have investigated the types of VGCCs present in brain vs other tissues have either used animal tissue, or have looked at only a few people, which is unlikely to be sufficient to address this question. Indeed, our preliminary studies already demonstrate that much remains unknown about the types of VGCCs that are present in the human brain.The research described here will help us to understand the key brain-enriched types of VGCC to target to improve the treatment of psychiatric illnesses, as well as investigating how genetic variation in the VGCCs increases risk for developing them. More broadly, they will also provide a test of how we can begin to move from genetic findings to new treatments.

在过去的几年里，我们在理解精神分裂症和双相情感障碍(也称为躁郁症)等精神疾病的遗传基础方面取得了实质性进展。人们希望，也经常声称，这些知识将导致对这些疾病的生物学和新疗法的洞察。然而，这一论点缺乏具体的例子。这项研究将开始检验我们如何通过关注最近遗传学研究中最有希望的一组分子：电压门控钙通道(VGCC)来检验我们如何从遗传洞察转向新的治疗方法。钙是一种重要的信号分子，在大脑功能中发挥着关键作用。长期以来，有证据表明，双相情感障碍患者存在钙功能异常。最近的遗传学研究表明，这些异常可能部分是由VGCC功能的改变引起的。这些通道成为治疗双相情感障碍和其他与这些通道有关的精神障碍的有吸引力的药物靶点。然而，许多不同类型的VGCC是由有限数量的VGCC基因产生的，并且缺乏关于人类大脑中存在的VGCC的确切类型的信息，以及这些通道在精神障碍和这些疾病的遗传风险较高的人中是如何改变的。我们也不知道关键的大脑VGCC与身体其他部位的VGCC有什么不同。这笔赠款将直接回答这三个问题，方法是确定与其他身体组织相比，人类大脑中存在和丰富的VGCC，并研究它们是如何与精神疾病的遗传风险以及疾病本身相关的变化的。这些研究将利用已经收集的大量数据，其中一些数据我们可以独一无二地获得。我们将把对这些现有数据集的分析与前沿的实验研究结合起来。至关重要的是，我们的分析和实验都将使用人脑组织。这是至关重要的，因为与其他类型的身体组织相比，单个基因产生的不同分子的数量在人类中比在其他物种中要高得多，特别是在人脑中。大多数研究大脑和其他组织中存在的VGCC类型的研究要么使用了动物组织，要么只研究了几个人，这不太可能足以解决这个问题。事实上，我们的初步研究已经证明，关于人脑中存在的VGCC的类型仍有许多未知之处。这里描述的研究将帮助我们了解VGCC的关键脑富集型，以改善精神疾病的治疗，并调查VGCC的基因变异如何增加发生这些疾病的风险。更广泛地说，它们还将测试我们如何开始从基因发现转向新的治疗方法。

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）

The Emerging Neurobiology of Bipolar Disorder.

DOI：
10.1016/j.tins.2017.10.006
发表时间：
2018-01
期刊：
Trends in neurosciences
影响因子：
15.9
作者：
Harrison PJ;Geddes JR;Tunbridge EM
通讯作者：
Tunbridge EM

Long read sequencing reveals novel isoforms and insights into splicing regulation during cell state changes.

DOI：
10.1186/s12864-021-08261-2
发表时间：
2022-01-10
期刊：
BMC genomics
影响因子：
4.4
作者：
Wright DJ;Hall NAL;Irish N;Man AL;Glynn W;Mould A;Angeles AL;Angiolini E;Swarbreck D;Gharbi K;Tunbridge EM;Haerty W
通讯作者：
Haerty W

Brain-penetrant calcium channel blockers are associated with a reduced incidence of neuropsychiatric disorders.