Survival signaling in CNS neurons exposed to DNA damage

暴露于 DNA 损伤的 CNS 神经元中的生存信号

基本信息

批准号：
7416641
负责人：
MICHAL HETMAN
金额：
$ 25.79万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-15 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7416641
关键词：
Address Adverse effects Affect Alzheimer&apos s Disease Antineoplastic Agents Apoptosis Appendix CPDD protocol Camptothecin Cell Death Central Nervous System Neoplasms Cerebellum Cessation of life Cisplatin Couples Cyclic AMP Cyclophosphamide Cytarabine DNA Damage DNA Repair DNA strand break Data Disease Dissection Drug Delivery Systems Evaluation Genomics Genotoxic Stress Goals Hippocampus (Brain)Injury Institutes Intercalating Agents International Light Link Longevity Mediating Minor Mitogen-Activated Protein Kinase 3 Molecular and Cellular Biology N-Methyl-D-Aspartate Receptors Nervous system structure Neurologic Neurons Operative Surgical Procedures Outcome Oxidative Stress Parkinson Disease Pathology Pathway interactions Pharmaceutical Preparations Poland Publishing Rattus Regulation Research Research Personnel Signal Pathway Signal Transduction Spinal Ganglia Stimulus Stroke System Testing Toxic effect Universities base cancer therapy drug development improved irradiation nervous system disorder neuron apoptosis neuron loss neuronal survival neurotoxic neurotoxicity novel nucleoside analog post-doctoral training repaired response small molecule therapy development

项目摘要

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.

描述（由申请人提供）：神经元是损害刺激的靶标，这可能会引发细胞死亡，因此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挑战的微小损害幸存下来。因此，人们可以提出存在一种机制，该机制有助于神经元在侮辱后生存最初的损伤并恢复适当的功能。识别这种机制可能会导致疗法的发展，这些治疗将利用内在的神经元防御机制对抗神经系统疾病。中枢神经系统中重要的有害刺激是氧化应激。它至少部分通过DNA的损伤而造成其毒性作用，其完整性对于适当的神经元存活至关重要。实际上，神经元对DNA损伤非常敏感。有趣的是，用于癌症治疗的DNA破坏药物经常会产生神经副作用。我们最近发表的结果表明，细胞外信号调节激酶1/2（ERK1/2）在大鼠皮质神经元中通过神经毒性DNA破坏药物Cisplatin（CPDD）激活（J Biol Chem 278：436663-43671）。此外，我们发现ERK1/2途径的抑制会增强对CPDD的毒性反应。因此，我们提案的总体目的是检验一个假设，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）识别ERK1/2介导的防止DNA损伤的保护的机制来实现这一目标，（ii）解剖ERK1/2通过ERK1/2链接DNA损伤和生存信号的途径，（iii）鉴定可以增强Neurons中ERK1/2通过（IV）评估ERK1/ERNA的ERK1/2的多样性的因素，以增强ERK1/2的防御信号传导。为了实现该建议，我们将使用培养的大鼠原发性神经元。拟议的研究可能导致鉴定出用于治疗神经系统疾病和/或癌症治疗有害神经系统副作用的新药物靶标。