Role of Ca2+-dependent mitochondrial and endoplasmic reticulumdynamics for disease progression and neuroprotection in a model ofmultiple sclerosis.

Ca2 依赖性线粒体和内质网动力学在多发性硬化症模型中疾病进展和神经保护中的作用。

• 批准号: 280875357
• 负责人: Professor Dr. Hilmar Bading
• 金额: --
• 依托单位: Anatomie I - Klinische Neuroanatomie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/280875357?language=en
• 关键词: Role; Ca2+; dependent; mitochondrial; endoplasmic

Mitochondria are integral for cellular function and survival. They generate ATP for cellular energy homeostasis, act as a Ca2+ sink and source to influence cellular Ca2+ signaling, and are key hubs for necrotic and apoptotic signaling networks. Accordingly, aberrant mitochondrial function is key to many neurodegenerative and neuroinflammatory diseases. Mitochondrial function depends on proper regulation of intra-mitochondrial Ca2+ levels, which in turn are tightly linked to cellular Ca2+ transients. Research from members of this Research Unit as well as from other labs has provided evidence for disturbed cellular Ca2+ homeostasis in multiple sclerosis. Given the tight coupling of cellular and mitochondrial Ca2+ levels, we hypothesize that mitochondrial Ca2+ dysregulation contributes to multiple sclerosis disease progression. In this project, we thus want to investigate the relationship between mitochondrial Ca2+ signaling, mitochondrial metabolic function, and neuronal degeneration in the rat experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis and optic neuritis. We plan to use genetically encoded fluorescent indicators to comprehensively analyse mitochondrial Ca2+ signaling and metabolic function in acute retinal slices from control and EAE animals. These novel indicators allow dynamic and quantitative imaging with single cell and subcellular resolution and thus provide information that cannot be obtained using conventional biochemical methods. Finally, by manipulating the expression levels of recently identified mitochondrial Ca2+ transporter proteins we aim at restoring mitochondrial Ca2+ homeostasis, metabolic function, and cell survival in the EAE model of multiple sclerosis.

线粒体对于细胞功能和存活是不可或缺的。它们产生ATP用于细胞能量稳态，作为Ca2+汇和源影响细胞Ca2+信号传导，并且是坏死和凋亡信号传导网络的关键枢纽。因此，异常的线粒体功能是许多神经退行性和神经炎性疾病的关键。线粒体功能依赖于线粒体内Ca2+水平的适当调节，而线粒体内Ca2+水平又与细胞Ca2+瞬变密切相关。该研究单位成员以及其他实验室的研究为多发性硬化症中细胞Ca2+稳态紊乱提供了证据。鉴于细胞和线粒体Ca2+水平的紧密耦合，我们假设线粒体Ca2+失调有助于多发性硬化症的进展。因此，在本项目中，我们希望研究线粒体Ca2+信号转导，线粒体代谢功能和神经元变性之间的关系在多发性硬化和视神经炎的大鼠实验性自身免疫性脑脊髓炎（EAE）模型。我们计划使用基因编码的荧光指示剂来全面分析对照组和EAE动物急性视网膜切片中的线粒体Ca2+信号传导和代谢功能。这些新的指标允许动态和定量成像与单细胞和亚细胞分辨率，从而提供信息，不能使用常规的生化方法获得。最后，通过操纵最近发现的线粒体Ca2+转运蛋白的表达水平，我们的目标是恢复线粒体Ca2+稳态，代谢功能，和细胞存活在多发性硬化的EAE模型。