Liberation of Intracellular Zinc and Neuronal Cell Death

在神经退行性疾病中，细胞内锌离子调节失调与神经元损伤密切相关 出现在中风、创伤和癫痫中。我们的研究小组首次提出了细胞内锌离子的释放 通过氧化和亚硝化应激结合蛋白质是一种关键的和普遍存在的触发因素 在这些和其他神经性疾病中神经细胞死亡过程的激活。在完成的工作中 在这笔赠款的第一个资助期，我们描述了由以下因素引起的细胞死亡信号级联 细胞内锌离子的释放，并在体内证明了这种金属在神经细胞内的损伤积累。 未见突触锌离子释放。完成并出版了几乎所有最初提议的 实验使我们能够继续扩大我们在这一新颖和令人兴奋的研究领域的工作。在……里面 这一竞争性更新应用我们提出：1)建立细胞内锌离子的机制。 释放激活特定的MAPK依赖的细胞死亡信号通路。通过这些研究，我们的目标是 描述锌离子启动不同信号转导过程的过程。2)调查 调节锌离子调控的神经元基因表达的因素以解决影响锌离子的条件 缓冲系统，最终，锌离子细胞的动态平衡。这些研究的目的是阐明 神经元中锌离子介导的基因表达的特性，这是一个相对未被探索但至关重要的领域 研究的成果。3)确定细胞内锌离子释放所激活的分子细胞死亡途径。 活体，揭开这种金属解放的内生刺激。我们的长期目标是 详细描述解放后导致神经细胞死亡的分子信号级联 胞内锌离子。因此，这些研究的结果可能会为治疗创造新的途径 对大量与氧化和亚硝酸盐相关的神经退行性疾病的干预 受伤。 与公共卫生的相关性。这些研究的结果将提供有关 导致一系列神经疾病的细胞机制，包括中风、创伤和癫痫。 有了这些信息，我们希望发现新的治疗策略来预防或阻止癌症的进展 这些和其他神经退行性疾病。

Dysregulation of cellular Zn2+ has been tightly linked to neuronal injury in neurodegenerative conditions present in stroke, trauma and epilepsy. Our group first suggested that Zn2+ released from intracellular binding proteins by oxidative and nitrosative stress represents a critical and ubiquitous trigger for the activation of neuronal cell death processes in these and other neurological disorders. In work performed during the first funding period of this grant, we characterized cell death signaling cascades resulting from ntracellular Zn2+ liberation, and demonstrated in vivo injurious intraneuronal accumulation of this metal in the absence of synaptic Zn2+ release. The completion and publication of nearly all of the originally proposed experiments has allowed us to continue to expand our work in this novel and exciting area of research. In this competitive renewal application we propose: 1) To establish the mechanism by which intracellular Zn2* release activates specific MAPK-dependent cell death signaling pathways. With these studies, we aim to characterize the process by which Zn2+ can initiate divergent signaling processes. 2) To investigate the factors that modulate Zn2+-regulated neuronal gene expression in order to resolve conditions affecting Zn2+ buffering systems and, ultimately, Zn2+ cellular homeostasis. These studies aim to elucidate the fundamental properties of Zn2+-mediated gene expression in neurons, a relatively unexplored but critically important area of research. And 3) to determine the molecular cell-death pathway activated by intracellular Zn2+ release in vivo and uncover the endogenous stimulus for the liberation of this metal. Our long-term objectives are to characterize in detail the molecular signaling cascades leading to neuronal cell death following the liberation of intracellular Zn2+. As such, results of these studies will likely generate new avenues for therapeutic intervention in the large number of neurodegenerative disorders associated with oxidative and nitrosative injury. Relevance to public health. Results from these studies will provide fundamental information about the cellular mechanisms responsible for a host of neurological disorders, including stroke, trauma and epilepsy. With this information, we hope to uncover novel therapeutic strategies to prevent or halt the progression of these and other neurodegenerative conditions.