Liberation of Intracellular Zinc and Neuronal Cell Death

描述（由申请人提供）：细胞Zn2+的失调与中风、创伤和癫痫等神经退行性疾病中的神经元损伤密切相关。我们的研究小组首先提出，氧化和亚硝化应激从细胞内结合蛋白释放的Zn2+是这些和其他神经系统疾病中神经元细胞死亡过程激活的关键和普遍存在的成分。在本基金的第一个资助期进行的工作中，我们描述了伴随细胞内Zn2+释放的细胞死亡信号级联反应，并证明了在缺乏突触Zn2+释放的情况下，这种金属在体内的损伤性神经元内积累。几乎所有最初提出的实验的完成和发表，使我们能够继续扩大我们在这个新颖和令人兴奋的研究领域的工作。在这个竞争性更新应用中，我们提出：1)建立细胞内Zn2+释放激活特定的mapk依赖性细胞死亡信号通路的机制。通过这些研究，我们的目标是最终表征Zn2+可以启动发散信号传导过程的过程。2)研究Zn2+调控神经元基因表达的调节因素，以解决影响Zn2+缓冲系统的条件，并最终解决Zn2+细胞稳态。这些研究旨在阐明Zn2+介导的神经元基因表达的基本特性，这是一个相对未被探索但至关重要的研究领域。3)在体内确定细胞内释放Zn2+激活的分子细胞死亡途径，揭示该金属释放的内源性刺激。我们的长期目标是详细描述细胞内Zn2+释放后导致神经元细胞死亡的分子信号级联反应。因此，这些研究的结果可能会为大量与氧化和亚硝化损伤相关的神经退行性疾病的治疗干预提供新的途径。公共卫生相关性：这些研究的结果将提供有关导致一系列神经系统疾病（包括中风、创伤和癫痫）的细胞机制的基本信息。有了这些信息，我们希望发现新的治疗策略来预防或阻止这些和其他神经退行性疾病的进展。

DESCRIPTION (provided by applicant): 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 component in 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 accompanied by intracellular 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 eventually 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. PUBLIC HEALTH RELEVANCE: 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.