MITOCHONDRIA, OXIDATIVE STRESS AND NEURONAL APOPTOSIS: BIOCHEMICAL, CELLULAR AND PHARMACOLOGICAL APPROACHES

我们的目标是了解神经细胞在各种压力和损伤后死亡的详细过程。我们的目标还在于开发保护细胞免受这种死亡的新方法。神经细胞的死亡在帕金森病、亨廷顿病、运动神经元病等一系列神经退行性疾病中起着重要的作用。细胞死亡的一个普遍原因是通常在神经细胞之间传递信号的递质的作用，但在应激和损伤的情况下，递质会引起神经细胞的过度刺激而导致死亡（兴奋性毒性）。线粒体是细胞的组成部分，通常为细胞提供能量以执行其各种功能；但在应激条件下，线粒体在导致细胞死亡的细胞决策过程中扮演着控制者的角色。此外，线粒体在神经退行性疾病中发挥着重要作用，因为它们是引起细胞损伤的称为自由基的破坏性氧衍生物的来源。线粒体也参与由兴奋性毒性引起的死亡。为了了解神经细胞死亡过程的详细机制，我们将使用来自实验室小鼠大脑的培养神经细胞，包括正常小鼠和神经退行性疾病模型小鼠。引起兴奋性毒性的递质类似物会引起导致死亡的损伤。我们将集中研究死亡过程中涉及线粒体的那些方面，因为这将使我们能够测试一系列抗氧化剂，这些抗氧化剂有望导致神经细胞损伤的新药物治疗。这些化合物中含有针对线粒体的新型抗氧化剂。该项目将heart教授在神经科学和药理学方面的专业知识与Nagley教授在生物化学方面的技能，特别是在线粒体和细胞死亡研究方面的技能结合起来，以多学科的方式解决这一重要的医学研究问题。

Our goal is to understand the detailed process whereby nerve cells die after various stresses and injury. We aim also to develop novel ways of protecting cells against such death. The death of nerve cells plays an important role in a series of neurodegenerative diseases, such as Parkinson's, Huntington's and Motor Neurone Diseases. One prevalent cause of cell death arises from the action of transmitters that normally signal between nerve cells but which, under conditions of stress and injury, cause overstimulation of the nerve cells leading to death (excitotoxicity). Mitochondria are component of cells normally providing energy for the cell to carry out its various functions; but under stress conditions mitochondria act as controllers in cellular decision-making processes leading to cell death. Moreover, mitochondria are known to play an important role in neurodegenerative diseases, as they are a source of damaging oxygen derivatives called free radicals that cause cell injury. Mitochondria are also involved in death resulting from excitotoxicity. In order to understand the detailed mechanism of the nerve cell death process, we will use cultured nerve cells from the brains of laboratory mice, including both normal mice and those that are models of neurodegenerative disease. Injury leading to death will be induced by analogues of the transmitters that cause excitotoxicity. We will concentrate the those aspects of the death process that involve mitochondria, as this will enable us to test a range of antioxidants that can be expected to lead to new drug treatments for neuronal cell injury. Included in these compounds are novel antioxidants that are targeted to mitochondria. This project brings together the expertise in neuroscience and pharmacology of Professor Beart with the skills in biochemistry of Professor Nagley, particularly in mitochondrial and cell death research, to address this important medical research problem in a multidisciplinary manner.