DNA Based Repair and MAP kinases

基于 DNA 的修复和 MAP 激酶

• 批准号: 7084844
• 负责人: Min Wu
• 金额: $ 6.98万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-10 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7084844
• 关键词: DNA binding protein; DNA damage; DNA repair; DNA replication; adduct; apoptosis; cell cycle; enzyme activity; enzyme mechanism; gene expression; gene targeting; hyperoxia; laboratory mouse; laboratory rat; mitogen activated protein kinase; protein protein interaction; protein structure function

DESCRIPTION (provided by applicant): Endogenous and environmental oxidation can cause DMA damage along with other organelle injury. For example, hyperoxia is a main therapeutics for acute lung failure but also causes lung cell toxicity. Since treatment of hyperoxic toxicity and other oxidation is largely supportive and natural defense mechanisms are easily defeated, development of new therapeutic strategies is warranted. Our preliminary data indicates that hyperoxia induces apoptosis associated with activation of mitogen-activated protein kinases (MARK, p38 and ERK1/2). We have also found that DNA base excision repair (BER) proteins can reverse oxidative DMA damage. However, it is unclear whether BER proteins interact with signaling proteins such as MARK. The objective of this application is to determine roles of BER in hyperoxic DNA damage and the regulatory mechanism, particularly interactions of BER proteins with MARK. Our central hypothesis is that BER proteins may regulate or interact with the MARK pathway to reverse DNA damage. Hyperoxia injured cells must either cease replication due to cell cycle arrest or replicate with a mutant form of DNA. Thus, DNA repair is urgently needed. Failure to repair the DNA damage results in genetic disintegration, apoptotic cell death, and an ultimate alveolar breakdown. MARK may help efficiently repair DNA damage, thus a critical way to reduce oxidative toxicity. The rationale is that additional knowledge of BER interacting with other signaling proteins would provide a foundation to better use BER DNA repair proteins to prevent oxidative injury. To test our hypothesis, we propose the following Specific Aims: #1 To identify hyperoxia-induced DNA lesions and alterations of MARK activity; #2 To evaluate role of BER proteins in regulating MARK activity. The significance is that regulation of BER repair and signaling proteins may be potentially useful for counteracting various oxidative damage to lung cells, including chemotherapeutics and heavy metals, such as cadmium.

描述（由申请人提供）：内源性和环境氧化可能会在其他细胞器损伤中造成DMA损伤。例如，高氧是急性肺衰竭的主要治疗方法，但也会引起肺部细胞毒性。由于高氧毒性和其他氧化的治疗在很大程度上是支持性的，并且很容易被击败，因此有必要开发新的治疗策略。我们的初步数据表明，高氧诱导与有丝分裂原激活蛋白激酶激活相关的凋亡（Mark，P38和ERK1/2）。我们还发现，DNA碱基切除修复（BER）蛋白可以逆转氧化DMA损伤。但是，尚不清楚BER蛋白是否与信号蛋白（如Mark）相互作用。该应用的目的是确定BER在高氧化DNA损伤和调节机制中的作用，尤其是BER蛋白与MARK的相互作用。我们的中心假设是，BER蛋白可以调节或与Mark途径相互作用，以反向DNA损伤。高氧损伤细胞必须由于细胞周期停滞而停止复制，或者用突变形式的DNA复制。因此，迫切需要DNA修复。无法修复DNA损伤会导致遗传崩解，凋亡细胞死亡和最终的肺泡分解。 MARK可能有助于有效修复DNA损伤，因此是降低氧化毒性的关键方法。理由是，与其他信号蛋白相互作用的其他知识将为更好地使用BER DNA修复蛋白提供基础，以防止氧化损伤。为了检验我们的假设，我们提出了以下特定目的：＃1确定高氧诱导的DNA病变和Mark活性的改变； ＃2评估BER蛋白在调节标记活性中的作用。意义在于，对BER修复和信号蛋白的调节可能有可能对肺细胞（包括化学治疗剂和重金属）（例如镉）的各种氧化损伤有用。