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

• 批准号: 8638191
• 负责人: LECH Kiedrowski
• 金额: $ 18.45万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8638191
• 关键词: Acidosis; Acids; Address; Adenine Nucleotides; Affinity; Apoptosis; Area; Binding; Brain Injuries; Brain Ischemia; Buffers; Cause of Death; Cell-Free System; Cells; Cessation of life; Characteristics; Chelating Agents; Chelation Therapy; Complex; Data; Development; Drops; FluoZin-3; Fluorescence; Future; Glucose; Goals; Hippocampus (Brain); Intercept; Ions; Ligands; Measures; Memory impairment; Methods; Mitochondria; Monitor; Mus; Neurons; Outcome; Oxygen; Play; Production; Proteins; Protons; Research; Role; Source; Specific qualifier value; Stroke; Testing; Time; Zinc; chelation; deprivation; design; follow-up; improved; in vivo; neurotoxic; novel; novel strategies; prevent; public health relevance; success; therapy development

Project Summary/Abstract 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 affinity 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.

项目总结/摘要 升高的细胞内游离Zn 2+浓度（[Zn 2 +]i）已经被牵连在由以下引起的神经元死亡中： 中风因此，恢复低[Zn 2 +]i的疗法有可能改善中风的结局。的 这项研究的目的是设计这样一种疗法。对海马神经元的初步研究表明 类似于中风期间发生的细胞内酸化导致[Zn 2 +]i升高， 从细胞内储存释放。我们将确定低亲和力Zn 2+配体的作用，如腺嘌呤 核苷酸，在这些[Zn 2 +]i升高，并建立是否可以通过特定的改善神经元的活力， 螯合酸诱导的[Zn 2 +]i升高。特别地，我们将设计一种Zn 2+螯合的方法， 特别针对这些酸诱导的[Zn 2 +]i升高。这项研究将在小学进行。 海马神经元。目的1将阐明哪些低亲和力的细胞内Zn 2+配体释放该离子 当pH值下降到冲程特征范围时。在目标2中，将开发一种方法， 螯合酸诱导的[Zn 2 +]i升高。目的3将确定这种Zn 2+螯合方法是否改善 神经元在缺氧缺糖环境下的存活能力。如果是这样，我们的方法将提供一个 开发治疗的框架，以抵消中风期间[Zn 2 +]i过度升高。