Regulation of excitotoxicity by ZnT1

ZnT1 对兴奋性毒性的调节

• 批准号: 10032716
• 负责人: Elias Aizenman
• 金额: $ 41.22万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10032716
• 关键词: Acute; Anniversary; Area; Brain; Cell Death; Cell Death Signaling Process; Cells; Chronic; Clinical Trials; Data; Development; Experimental Designs; Future; Glutamates; In Vitro; Injury; Ischemic Preconditioning; Kainic Acid Receptors; Link; Mediating; Metals; Mind; Modeling; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurodegenerative Disorders; Neuronal Injury; Neurons; Peptides; Play; Process; Rattus; Regulation; Research; Research Project Grants; Retina; Rodent Model; Role; Seminal; Signal Pathway; Solid; Synapses; Testing; Time; Up-Regulation; Work; Zinc; base; design; excitotoxicity; fundamental research; in vivo; in vivo Model; innovation; mouse model; neuron loss; neuroprotection; novel strategies; preconditioning; programs; receptor; receptor function; research and development; research study; response; success; therapeutic target; tissue culture; tool; translational approach; virtual; zinc-binding protein

This year marks the 50th anniversary of John Olney’s seminal work that introduced the concept of excitotoxicity as a mechanism for neuronal cell death. Since that time, fundamental research on the pathophysiological activation of NMDA receptors has played a central role in our understanding of excitotoxic cellular signaling pathways, leading to the discovery of many potential therapeutic targets in the treatment of acute or chronic/progressive neurodegenerative disorders. Despites countless efforts, however, translational strategies aimed at inhibiting or regulating NMDA receptor-mediated excitotoxic injury have repeatedly failed in clinical trials, leaving only very few potential applications viable today. Nonetheless, highly innovative approaches in this important area of research could still yield tangible advances in the field of neuroprotection. We this in mind, we introduce here a previously unrecognized modulator of NMDA receptor-mediated excitotoxicity, namely, the ZnT1 (Slc30a1) zinc transporter. We present preliminary data showing that the interaction between ZnT1 and the highly zinc sensitive NMDA receptor subunit GluN2A strongly dictate the inhibitory, regulatory function of the metal on the receptor. Moreover, we reveal the development of a cell-penetrating peptide designed to specifically reduce the interaction between ZnT1 and GluN2A influences NMDA receptor-mediated synaptic responses. We tailor the proposed work by taking advantage of an endogenous neuronal mechanism of zinc-dependent excitotoxic tolerance, and utilize both in vitro and in vivo experimental approaches to achieve the proposed aims, which are: i) to investigate the role of the GluN2A-ZnT1 interaction in regulating NMDA excitotoxicity in vitro, and ii) to establish the role of ZnT1 upregulation and increased GluN2A-ZnT1 interaction in an in vivo model of ischemic preconditioning. If successful, the work proposed in this Exploratory/Development Research Grant (R21) proposal will define an novel approach to regulate NMDA receptor-mediated excitotoxic injury, with translational potential in future work.

今年是约翰·奥尔尼提出兴奋性毒性概念的开创性工作50周年 作为神经细胞死亡的一种机制。从那时起，病理生理学的基础研究 NMDA受体的激活在我们对兴奋性毒性细胞信号的理解中起着核心作用 途径，导致许多潜在的治疗靶点的发现，在治疗急性或 慢性/进行性神经退行性疾病。然而，尽管付出了无数的努力，翻译策略 旨在抑制或调节NMDA受体介导的兴奋性毒性损伤在临床上屡屡失败 试验，只留下很少的潜在应用今天可行。尽管如此，高度创新的方法在 这一重要的研究领域仍然可以在神经保护领域取得切实的进展。我们考虑到这一点， 我们在这里介绍了一种以前未知的NMDA受体介导的兴奋性毒性的调节剂，即 锌转运蛋白：锌转运蛋白。我们给出的初步数据表明，锌离子和锌离子的相互作用 高度锌敏感的NMDA受体亚单位GluN2A强烈地决定了细胞的抑制和调节功能 感受器上的金属。此外，我们揭示了一种细胞穿透性多肽的发展，该多肽旨在特异性地 减少ZnT1和GluN2A之间的相互作用会影响NMDA受体介导的突触反应。我们 通过利用锌依赖的内源性神经机制来定制拟议的工作 兴奋毒性耐受性，并利用体外和体内实验方法来实现所提出的目标， 它们是：1)研究GluN2A-ZnT1相互作用在体外调节NMDA兴奋性毒性中的作用。 以及ii)在小鼠的体内模型中，建立ZnT1上调和GluN2a-ZnT1相互作用增加的作用。 缺血预适应。如果成功，这项探索性/发展性研究补助金中建议的工作 (R21)提案将定义一种新的方法来调节NMDA受体介导的兴奋性毒性损伤， 在未来工作中的翻译潜力。