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导致 DMA 损伤以及其他细胞器损伤。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，并且自然防御机制很容易被击败，因此有必要开发新的治疗策略。我们的初步数据表明，高氧诱导与丝裂原激活蛋白激酶（MARK、p38 和 ERK1/2）激活相关的细胞凋亡。我们还发现 DNA 碱基切除修复 (BER) 蛋白可以逆转氧化 DMA 损伤。然而，尚不清楚 BER 蛋白是否与 MARK 等信号蛋白相互作用。本应用的目的是确定 BER 在高氧 DNA 损伤中的作用及其调节机制，特别是 BER 蛋白与 MARK 的相互作用。我们的中心假设是 BER 蛋白可能调节 MARK 通路或与 MARK 通路相互作用以逆转 DNA 损伤。高氧损伤的细胞要么因细胞周期停滞而停止复制，要么以突变形式的 DNA 进行复制。因此，迫切需要DNA修复。 DNA 损伤修复失败会导致基因崩解、细胞凋亡和最终肺泡破裂。 MARK可能有助于有效修复DNA损伤，因此是减少氧化毒性的关键方法。其基本原理是，关于 BER 与其他信号蛋白相互作用的更多知识将为更好地使用 BER DNA 修复蛋白预防氧化损伤奠定基础。为了检验我们的假设，我们提出以下具体目标： #1 识别高氧诱导的 DNA 损伤和 MARK 活性的改变； #2 评估 BER 蛋白在调节 MARK 活性中的作用。其意义在于，BER 修复和信号蛋白的调节可能有助于抵消肺细胞的各种氧化损伤，包括化疗药物和镉等重金属。