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Mechanisms and implications of intracellular Zn2+ release in acidified neurons

酸化神经元细胞内 Zn2 释放的机制和意义

基本信息

批准号：
8720082
负责人：
LECH Kiedrowski
金额：
$ 15.79万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Elevated intracellular free Zn2+ concentrations ([Zn2+]i) have been implicated in the neuronal death caused by stroke. Therefore, a therapy that restores low [Zn2+]i has the potential to improve the outcome of stroke. The goal of proposed research is to design such a therapy. Preliminary studies on hippocampal neurons indicate that an intracellular acidification similar to that taking place during stroke causes [Zn2]i elevations due to Zn2+ release from intracellular stores. We will determine the role of low affinit Zn2+ ligands, such as adenine nucleotides, in these [Zn2+]i elevations and establish whether neuronal viability can be improved by a specific chelation of acid-induced [Zn2+]i elevations. In particular, we will design a method of Zn2+ chelation that specifically targets these acid-induced [Zn2+]i elevations. The research will be conducted on primary hippocampal neurons from mice. Aim 1 will clarify which low affinity intracellular Zn2+ ligands release this ion when the pH drops into a stroke-characteristic range. In Aim 2, a method will be developed to specifically chelate acid-induced [Zn2+]i elevations. Aim 3 will determine whether this method of Zn2+ chelation improves the viability of neurons exposed to oxygen and glucose-deprivation. If it does, our method will provide a framework for the development of therapy that counteracts excessive [Zn2+]i elevations during stroke.

描述(申请人提供)：细胞内游离锌离子浓度升高([锌2+]i)与中风引起的神经元死亡有关。因此，恢复低[Zn2+]i的治疗有可能改善卒中的结局。拟议研究的目标就是设计这样一种疗法。对海马神经元的初步研究表明，与中风时发生的细胞内酸化类似，由于细胞内储存的锌离子释放，导致[锌]i升高。我们将确定低亲和力的锌配体，如腺嘌呤核苷酸，在这些[锌]i升高中的作用，并确定是否可以通过特定的螯合酸诱导的[锌]i升高来提高神经元的存活率。特别是，我们将设计一种锌离子螯合的方法，专门针对这些酸诱导的[锌]i升高。这项研究将在小鼠的原代海马神经元上进行。目标1将阐明当pH下降时，哪些低亲和力的细胞内锌离子配体释放该离子进入具有中风特征的范围。在目标2中，将开发一种方法来特定地螯合由酸引起的[锌]i升高。目的3将确定这种锌离子络合的方法是否改善了暴露在缺氧和葡萄糖剥夺下的神经元的生存能力。如果是这样的话，我们的方法将为开发中和中风期间过度升高的[锌]i的治疗方法提供一个框架。