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DNA Based Repair and MAP kinases

基于 DNA 的修复和 MAP 激酶

基本信息

批准号：
7220609
负责人：
Min Wu
金额：
$ 6.78万
依托单位：
UNIVERSITY OF NORTH DAKOTA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-10 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7220609
关键词：
8-oxoguanine Acute Alveolar Apoptosis Apoptotic Base Excision Repairs Blood capillaries Cadmium Capillary Endothelial Cell Cell Cycle Arrest Cell Death Cell Line Cells Clinical Condition DNA DNA Adducts DNA Damage DNA Repair DNA lesion DNA repair protein DNA strand break Data Defense Mechanisms Development Disruption Edema Endothelial Cells Endothelium Epithelial Cells Epithelium Excision Repair Failure Foundations Gene Mutation Genetic Heavy Metals Hyperoxia Injury Left Lipids Liquid substance Lung Mediating Mitogen-Activated Protein Kinases Molecular Organelles Oxidants Oxygen Pathway interactions Patients Personal Satisfaction Pharmaceutical Preparations Process Protein Overexpression Proteins Radiation Reactive Oxygen Species Regulation Role Sampling Signal Transduction Signaling Protein Superoxides Testing Therapeutic Thinking Toxic effect Type I Epithelial Receptor Cell Type II Epithelial Receptor Cell Water adduct base capillary cell injury cigarette smoking cytotoxic cytotoxicity exhaust gene repair improved injured innovation interest interstitial knowledge base mitogen-activated protein kinase p38 mutant novel therapeutics oxidation oxidative DNA damage pathogen preclinical study pressure prevent repaired response

项目摘要

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损伤沿着其他细胞器损伤。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，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，高氧诱导细胞凋亡与丝裂原活化蛋白激酶（MARK，p38和ERK 1/2）的激活。我们还发现DNA碱基切除修复（BER）蛋白可以逆转氧化性DNA损伤。然而，目前还不清楚BER蛋白是否与信号蛋白如MARK相互作用。本申请的目的是确定BER在高氧DNA损伤中的作用和调节机制，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。高氧损伤的细胞必须要么由于细胞周期停滞而停止复制，要么用DNA的突变形式复制。因此，DNA修复是迫切需要的。不能修复DNA损伤导致遗传解体、凋亡性细胞死亡和最终的肺泡破裂。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。基本原理是BER与其他信号蛋白相互作用的额外知识将为更好地使用BER DNA修复蛋白来防止氧化损伤提供基础。为了验证我们的假设，我们提出了以下具体目标：#1鉴定高氧诱导的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。重要的是，BER修复和信号蛋白的调节可能有助于抵消对肺细胞的各种氧化损伤，包括化疗药物和重金属，如镉。