Liberation of Intracellular Zinc and Neuronal Cell Death

细胞内锌的释放和神经元细胞死亡

• 批准号: 8206868
• 负责人: Elias Aizenman
• 金额: $ 32.48万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2013-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8206868
• 关键词: Acute; Affect; Area; Binding Proteins; Brain; Buffers; Caspase; Cell Death; Cell Death Process; Cell Death Signaling Process; Cell Survival; Cessation of life; Chronic; Coculture Techniques; Embryo; Epilepsy; Event; Funding; Gene Expression; Generations; Goals; Grant; Health; Homeostasis; In Vitro; Injury; Investigation; Lead; Link; Mediating; Mediator of activation protein; Metallothionein; Metals; Microglia; Mitogen-Activated Protein Kinases; Modeling; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Injury; Neurons; Oxidants; Oxidative Stress; Pathway interactions; Positioning Attribute; Potassium Channel; Process; Production; Property; Protein Kinase C; Public Health; Publications; Rattus; Research; Role; Signal Pathway; Signal Transduction; Slice; Stimulus; Stroke; Synapses; System; Thalamic structure; Therapeutic Intervention; Trauma; Work; Zinc; computerized data processing; human MAPK14 protein; in vivo; in vivo Model; nervous system disorder; neuron loss; new therapeutic target; nitrosative stress; novel; novel therapeutics; prevent; programs; research study; voltage

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.

描述（由申请人提供）：细胞Zn 2+调节异常与卒中、创伤和癫痫中存在的神经退行性疾病中的神经元损伤密切相关。我们的小组首先提出，锌从细胞内结合蛋白的氧化和亚硝化应激释放代表一个关键的和普遍存在的组件在这些和其他神经系统疾病的神经细胞死亡过程的激活。在这项资助的第一个资助期内进行的工作中，我们表征了伴随细胞内Zn 2+释放的细胞死亡信号级联，并证明了在突触Zn 2+释放的情况下，这种金属在体内损伤性的神经元内积累。几乎所有最初提出的实验的完成和出版使我们能够继续扩大我们在这个新颖而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Zn 2+释放激活特异性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的过程中，Zn 2+可以启动不同的信号传导过程。2)研究调节Zn 2+调节的神经元基因表达的因素，以解决影响Zn 2+缓冲系统和最终影响Zn 2+细胞稳态的条件。这些研究旨在阐明锌离子介导的基因表达在神经元中的基本特性，这是一个相对未开发但非常重要的研究领域。3）确定体内细胞内Zn ~（2+）释放激活的分子细胞死亡途径，并揭示这种金属释放的内源性刺激。我们的长期目标是详细描述导致神经元细胞死亡的分子信号转导级联释放细胞内Zn 2+。因此，这些研究的结果可能会产生新的途径，用于治疗与氧化和亚硝化损伤相关的大量神经退行性疾病。公共卫生相关性：这些研究的结果将提供有关细胞机制的基本信息，这些细胞机制负责一系列神经系统疾病，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，以预防或阻止这些和其他神经退行性疾病的进展。