Survival signaling in CNS neurons exposed to DNA damage

描述（由申请人提供）：神经元是破坏性刺激的目标，这可能会引发细胞死亡，从而导致严重的神经系统疾病。有趣的是，大多数神经元在生命周期中受到轻微损伤后仍能存活。因此，人们可以提出存在一种机制，帮助神经元在初始损伤后存活并在损伤后恢复正常功能。这种机制的鉴定可能会导致开发利用内在神经元防御机制对抗神经系统疾病的治疗方法。氧化应激是中枢神经系统中一种重要的损伤性刺激。它至少部分地通过损伤DNA发挥其毒性作用，DNA的完整性对神经元的正常存活至关重要。事实上，神经元对DNA损伤非常敏感。有趣的是，用于癌症治疗的DNA损伤剂经常产生神经副作用。我们最近发表的结果表明，细胞外信号调节激酶1/2（ERK 1/2）在大鼠皮层神经元中被神经毒性DNA损伤药物顺铂（CPDD）激活（J Biol Chem 278：43663-43671）。此外，我们发现ERK 1/2通路的抑制增强了对CPDD的毒性反应。因此，我们的建议的总体目标是测试一个假设，即神经元DNA损伤激活ERK 1/2，以抑制神经元死亡，并加强修复的细胞损伤。我们将通过（i）识别ERK 1/2介导的保护DNA损伤的机制，（ii）解剖连接DNA损伤和ERK 1/2的存活信号传导的途径，（iii）识别可以增强神经元中ERK 1/2的防御信号传导的因子，最后通过（iv）评估ERK 1/2激活作为对不同形式DNA损伤的一般补偿反应来实现这一目标。为了实现这一提议，我们将使用培养的大鼠原代神经元。拟议的研究可能会导致识别新的药物靶点，用于治疗神经系统疾病和/或癌症治疗的有害神经系统副作用。

DESCRIPTION (provided by applicant): Neurons are targets for damaging stimuli, which may trigger cell death and in consequence serious neurological diseases. Interestingly, most neurons survive minor damages which they are challenged with during the life span. Therefore one can propose existence of a mechanism that helps neurons to survive the initial injury and resume proper functions after an insult. Identification of this mechanism may result in development of treatments that would harness the intrinsic neuronal defense machinery to combat against neurological diseases. An important damaging stimulus in the CNS is oxidative stress. It exerts its toxic effects at least in part through injury of DNA whose integrity is critical for proper neuronal survival. Indeed, neurons are very sensitive to DNA damage. Interestingly, DNA damaging agents that are used in cancer therapy frequently produce neurological side effects. Our recently published results indicate that Extracellular Signal Regulated Kinase 1/2 (ERK1/2) is activated in rat cortical neurons by a neurotoxic DNA-damaging drug, cisplatin (CPDD) (J Biol Chem 278:43663-43671). Furthermore, we have found that inhibition of ERK1/2 pathway enhances toxic response to CPDD. Consequently, the general aim of our proposal is testing a hypothesis that neuronal DNA damage activates ERK1/2 to suppress neuronal death and to enhance repair of the cellular damage. We will approach this goal by (i) identification of the mechanism behind ERK1/2 mediated protection against DNA damage, (ii) dissection of the pathway linking DNA damage and survival signaling by ERK1/2, (iii) identification of factors which could enhance defensive signaling by ERK1/2 in neurons and finally by (iv) evaluation of ERK1/2 activation as a general compensatory response to diverse forms of DNA injury. To realize the proposal we will use cultured rat primary neurons. The proposed research may result in identification of new drug targets for treatment of neurological diseases and/or deleterious neurological side effects of cancer therapy.