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P2X4 receptor and chronic pain - developing novel pharmacological tools to target P2X4 in the central nervous system

P2X4 受体和慢性疼痛 - 开发针对中枢神经系统中的 P2X4 的新型药理学工具

基本信息

批准号：
1794654
负责人：
金额：
--
依托单位：
University of East Anglia
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-1794654
关键词：
P2X4 receptor chronic pain developing

项目摘要

Venoms from snakes, spiders, scorpions and marine animals contain a staggering array of peptides and small molecules. Purification of peptide toxins have revolutionised the understanding of the structure and function of ion channels in vertebrates. These highly specific peptide toxins mediate their actions through binding to ion channels and either blocking or enhancing their activity. Typically these peptides are highly potent and selective for individual ion channels, even individual isoforms, and as such these have the potential to be modified to develop new pharmacological tools for research and drug discovery. P2X4 is an important ligand-gated ion channel activated by extracellular ATP and is thought to play a critical role in the development of neuropathic pain. P2X4 regulates Brain Derived Neurotrophic Factor (BDNF) secretion from activated spinal cord microglia and causes alteration of dorsal horn neuronal excitability culminating in pathological pain. This project will identify and characterise a series of peptides isolated from spider venoms acting on the human P2X4 ligand-gated ion channel. The student will learn how to fractionate venoms using reverse phase HPLC to purify active peptide fractions and will characterise their effects using plate reader methods and patch clamp electrophysiology. We will use our novel modulators of P2X4 to investigate the role of this ion channel in microglial responses, in particular the role of P2X4 in secretion of BDNF from microglia using ELISA techniques.

蛇、蜘蛛、蝎子和海洋动物的毒液含有一系列令人震惊的多肽和小分子。多肽毒素的纯化彻底改变了人们对脊椎动物离子通道结构和功能的理解。这些高度特异的多肽毒素通过与离子通道结合并阻断或增强其活性来调节其作用。通常情况下，这些多肽对单个离子通道，甚至单个异构体都具有很高的效力和选择性，因此它们有可能被修饰，为研究和药物发现开发新的药理工具。P2X4是由细胞外ATP激活的一种重要的配体门控离子通道，被认为在神经病理性疼痛的发生发展中起着关键作用。P2X4调节活化的脊髓小胶质细胞分泌脑源性神经营养因子，引起背角神经元兴奋性的改变，最终导致病理性疼痛。该项目将鉴定和表征一系列从蜘蛛毒液中分离出来的作用于人类P2X4配体门控离子通道的多肽。学生将学习如何使用反相高效液相色谱分离毒液以纯化活性多肽部分，并将使用平板阅读器方法和膜片钳电生理学来表征其效果。我们将使用我们的新型调节剂P2X4来研究这个离子通道在小胶质细胞反应中的作用，特别是利用ELISA技术研究P2X4在小胶质细胞分泌BDNF中的作用。