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Elucidation of the physiological role of BARP, a new blocker of voltage-gated Ca2+ channels,in Purkinje cell

阐明 BARP（一种新的电压门控 Ca2 通道阻断剂）在浦肯野细胞中的生理作用

基本信息

批准号：
16K07360
负责人：
ベガンパスカル
金额：
$ 3.16万
依托单位：
Institute of Physical and Chemical Research
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2016
资助国家：
日本
起止时间：
2016 至无数据
项目状态：
已结题

项目摘要

The aim of this aborted project was to determine the contribution of a newly identified regulator of calcium channels, in neuronal synaptic plasticity. The regulator, named cBARP is highly expressed in some pyramidal neurons and in cerebellar Purkinje cells. In the initial phase of the project, the main investigator developed in parallel a Purkinje-specific inducible over-expression and a microRNA-based silencing strategy, to examine the contribution of this protein to calcium homeostasis in neurons. Concomitantly, though a collaboration with colleagues at A*Star (Singapore), we started to utilize a new conditional cBARP-KO transgenic mice, for specifically altering cBARP expression in Purkinje neuron, in vivo. The results obtained indicate that cBARP is a strong regulator of voltage-dependent calcium channels in neurons and profoundly affects neuronal development if expression is induced at early post-natal stage in neurons. The MiRNA-based silencing construct and strategy using recombinase-based conditional KO only showed moderate reduction of cBARP expression in the targeted neurons, far lower than the results previously obtained in test models. This may indicates a peculiar stability of cBARP (low turn-over) in Purkinje cells. The unfortunate disease and passing-away of Dr. Beguin changed the focus of the project from a long-term effort to one to be completed within the first half of FY2017.

这个流产的项目的目的是确定一个新发现的钙通道调节器在神经元突触可塑性中的作用。该调节因子名为cBARP，在一些锥体神经元和小脑浦肯野细胞中高度表达。在该项目的初始阶段，主要研究人员平行开发了浦肯野特异性诱导性过表达和基于microRNA的沉默策略，以研究这种蛋白质对神经元钙稳态的贡献。与此同时，通过与A* 星星（新加坡）的同事合作，我们开始利用新的条件性cBARP-KO转基因小鼠，在体内特异性改变浦肯野神经元中的cBARP表达。所获得的结果表明，cBARP是神经元中电压依赖性钙通道的强调节剂，并且如果在神经元中在出生后早期诱导表达，则会深刻地影响神经元发育。基于miRNA的沉默构建体和使用基于重组酶的条件性KO的策略仅显示靶向神经元中cBARP表达的中度降低，远低于先前在测试模型中获得的结果。这可能表明cBARP在浦肯野细胞中具有特殊的稳定性（低转换）。Beguin博士的不幸疾病和去世将该项目的重点从长期努力转变为将于2017财年上半年完成。