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，可能引发细胞死亡并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的轻微损伤都能存活下来。因此，我们可以提出存在一种机制，帮助神经元在最初的损伤中存活下来，并在损伤后恢复正常功能。识别这一机制可能会导致利用内在神经元防御机制来对抗神经系统疾病的治疗方法的发展。氧化应激是中枢神经系统中一种重要的破坏性刺激。它至少在一定程度上通过损伤DNA发挥其毒性作用，而DNA的完整性对神经元的正常存活至关重要。的确，神经元对DNA损伤非常敏感。有趣的是，用于癌症治疗的DNA损伤剂经常会产生神经系统副作用。我们最近发表的研究结果表明，细胞外信号调节激酶1/2 （ERK1/2）在大鼠皮质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ERK1/2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验证一个假设，即神经元DNA损伤激活ERK1/2以抑制神经元死亡并增强细胞损伤的修复。我们将通过(i)确定ERK1/2介导的DNA损伤保护背后的机制，（ii）解剖ERK1/2连接DNA损伤和生存信号的途径，（iii）确定可以增强神经元中ERK1/2防御信号的因素，最后（iv）评估ERK1/2激活作为多种形式DNA损伤的一般代偿反应。为了实现这一建议，我们将使用培养的大鼠初级神经元。拟议的研究可能导致确定新的药物靶点，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.