NEUROPROTECTION BY GROWTH FACTORS DURING NITRIC OXIDE TO

神经退行性疾病，无论是由遗传缺陷、创伤或其他侮辱引起的，都会导致长期的缺陷，严重影响生活质量。导致神经退行性变的机制很复杂，但反复出现的主题表明，不同类型的神经退行性疾病可能具有共同的机制。在之前的资助期间，我们在两个方面取得了重大进展：1)一氧化氮(NO)可能是缺血时神经元死亡的主要贡献者，2)生长因子和第二信使系统可以改变神经元对NO和缺血的敏感性。越来越清楚的是，NO可能在许多神经退行性疾病中发挥核心作用，包括亨廷顿舞蹈病、帕金森病和肌萎缩侧索硬化症。将NO造成的损害降至最低的信号系统有可能成为潜在的治疗药物。这一应用既关注无毒机制，也关注神经保护机制。它建立在前一个赠款期间的几个观察结果的基础上。我们想要确定由生长因子控制的信号通路是保护性的，以及哪些基因产物使神经元对无毒性更具抵抗力。我们还对确定由NO控制导致细胞死亡的毒性事件感兴趣。这笔赠款的具体目标是：具体目标1.确定ras/MAP激酶和RAC通路在保护无毒中的作用。具体目标2(A)。了解cGMP对海马神经元的毒性作用。具体目标2(B)。目的：确定一系列事件的重要性，包括cGMP的产生、cGMP门控非选择性阳离子通道(CGGCC)的激活以及cGMP依赖的蛋白激酶的激活在海马神经元对非毒性和缺血的敏感性中的重要性。具体目的3.利用表达-克隆方法分离编码无毒抗性蛋白的基因。我们的长期目标是了解NO在缺血和神经退行性疾病中的作用，了解生长因子和其他信号分子如何保护神经元免受NO的毒性影响，并将这些发现转化为治疗。

Neurodegenerative disorders, whether caused by genetic defects, trauma, or other insults, result in long term deficits that seriously compromise the quality of life. The mechanisms that lead to neurodegeneration are complex, but recurrent themes suggest different types of neurodegenerative disorders may share common mechanisms. During the previous grant period, we made significant progress in developing two ideas: 1) that NO (nitric oxide) could be a major contributor to neuron death during ischemia, and 2) that growth factors and second messenger systems could modify the sensitivity of neurons to NO and ischemia. It is becoming increasingly clear that NO may play a central role in a number of neurodegenerative diseases, including Huntington's Chorea, Parkinson's Disease, and Amyotrophic Lateral Sclerosis. Signalling systems that minimize the damage caused by NO have the potential are potential therapeutic agents. This application focuses both on the mechanism of NO-toxicity and on neuroprotective mechanisms. It builds on several observations from the previous grant period. We want to determine signaling pathways controlled by growth factors are protective and which gene products make neurons more resistant to NO-toxicity. We are also interested in determining the toxic events that are controlled by NO that lead to cell death. The specific aims of this grant are: Specific Aim 1. To determine the roles of the ras/MAP kinase and the rac pathways in protection against NO toxicity. Specific Aim 2(a). To understand the toxic effects of cGMP on hippocampal neurons. Specific Aim 2(b). To determine the importance of a cascade of events, including the production of cGMP, the activation of cGMP-gated non-selective cation channels (cGGCC), and the activation of the cGMP-dependent protein kinase in the sensitivity of hippocampal neurons to NO-toxicity and ischemia. Specific Aim 3. To isolate genes that encode proteins which confer resistance to NO toxicity by using an expression-cloning approach. Our long range goals are to understand the role of NO in ischemia and neurodegenerative disorders, to understand how growth factors and other signaling molecules can protect neurons from the toxic effects of NO, and to translate these discoveries into therapy.