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DNA Damage/Repair and Cell Death

DNA 损伤/修复和细胞死亡

基本信息

批准号：
7428843
负责人：
LEE J MARTIN
金额：
$ 28.77万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7428843
关键词：
ABL1 gene Acquired Immunodeficiency Syndrome Acute Adverse effects Age Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Apoptosis Apoptotic Applications Grants Ataxia-Telangiectasia-Mutated protein kinase Automobile Driving Base Excision Repairs Caspase Cell Death Cells Cerebral Ischemia Cessation of life Chronic Comet Assay Craniocerebral Trauma Cultured Cells DNA DNA Damage DNA Repair DNA Repair Disorder DNA Repair Enzymes DNA Single Strand Break DNA lesion Data Degradation Pathway Dependence Down Syndrome Embryo Enzymes Family Fluorescent in Situ Hybridization Genome Goals Grant Hybrids In Vitro Inherited Link Malignant Neoplasms Measures Mediating Mediator of activation protein Mitogen-Activated Protein Kinases Modeling Molecular Molecular Target Mus Necrosis Nerve Degeneration Neuroglia Neurologic Neurons Parkinson Disease Pathogenesis Pathway interactions Pattern Protein Kinase Regulation Role Signal Pathway Signal Transduction Signal Transduction Pathway Site Staging Stress Syndrome TP53 gene Testing Time Toxic effect Work age related base c-abl Proto-Oncogenes cancer therapy cancer type caspase-3 design human DNA damage human disease insight member nervous system disorder neuron loss research study response sensor

项目摘要

DESCRIPTION (provided by applicant): Neuronal cell death induced by DNA damage has been implicated in the pathogenesis of many acute and chronic neurological disorders in humans, and DNA damage-induced cell death is a fundamental principle driving therapy for many types of cancer. The major goal of the experiments in this grant proposal is to determine if DNA damage is a cause or consequence of neurodegeneration. Cultured embryonic mouse cortical neurons will be used as a model to study cause-effect links between specific types of DNA lesions and cell death and the mechanisms of DNA damage-induced apoptosis in young and mature neurons. In Specific Aim 1 we will identify lethal levels of DNA damage in neurons and the relationships between DNA damage level, DNA lesion type, and cell death pattern (apoptosis, necrosis, or hybrid) and will test the hypothesis that toxicity of DNA damaging agents on neurons is maturation-related. We will study if DNA damage occurs preferentially at specific sites within the neuronal genome using comet-FISH analysis. We will identify the major DNA repair and DNA degradation pathways in cortical neurons and will determine whether DNA repair is different in neurons at different stages of maturation. We will test the hypothesis that the dependence of DNA damage-triggered death on caspases and MARK signaling differs in neurons of different maturational states. In Specific Aim 2, we will evaluate upstream mechanisms that link DNA damage to downstream apoptosis mechanisms in cortical neurons. We will test the hypothesis that DNA damage-induced apoptosis in young and mature neurons is mediated by the ATM-p53 or cAbl-p53 signaling networks. In Specific Aim 3, we will determine if enforced expression of DNA repair enzymes that function in base excision repair can be neuroprotective. These experiments will provide important information on the toxicity of DNA damage in neurons, the specific types of DNA damage that can occur in neurons, the effects of DNA damage on neurons of different ages, and the molecular mechanisms that transduce DNA damage signals to apoptotic pathways in neurons. This work is relevant to human disease because it will contribute to the understanding of the pathobiology of DNA damage-induced neurodegeneration and to the identification of possible molecular targets for reducing the toxic and neurologic side-effects of cancer therapy.

描述(申请人提供)：DNA损伤导致的神经细胞死亡与人类许多急慢性神经疾病的发病机制有关，DNA损伤诱导的细胞死亡是许多类型癌症治疗的基本原则。这项拨款提案中的实验的主要目标是确定DNA损伤是神经变性的原因还是后果。培养的胚胎小鼠皮质神经元将作为模型，研究特定类型的DNA损伤与细胞死亡之间的因果联系，以及DNA损伤诱导年轻和成熟神经元凋亡的机制。在具体目标1中，我们将确定神经元中DNA损伤的致死性水平，以及DNA损伤水平、DNA损伤类型和细胞死亡模式(细胞凋亡、坏死或混合)之间的关系，并将检验DNA损伤剂对神经元毒性与成熟相关的假设。我们将使用彗星-FISH分析来研究DNA损伤是否优先发生在神经元基因组中的特定位置。我们将确定皮质神经元中主要的DNA修复和DNA降解途径，并将确定不同成熟阶段的神经元中DNA修复是否有所不同。我们将检验这一假设，即DNA损伤引发的死亡对caspase和Mark信号的依赖在不同成熟状态的神经元中是不同的。在特定的目标2中，我们将评估将DNA损伤与皮质神经元的下游凋亡机制联系起来的上游机制。我们将检验这一假设，即DNA损伤诱导的年轻和成熟神经元的凋亡是由ATM-P53或CABL-P53信号网络介导的。在特定的目标3中，我们将确定在碱基切除修复中起作用的DNA修复酶的强制表达是否具有神经保护作用。这些实验将提供关于神经元DNA损伤的毒性、神经元中可能发生的特定类型的DNA损伤、DNA损伤对不同年龄神经元的影响以及将DNA损伤信号转导到神经元中的凋亡途径的分子机制的重要信息。这项工作与人类疾病相关，因为它将有助于理解DNA损伤诱导的神经退行性变的病理生物学，并有助于确定可能的分子靶点，以减少癌症治疗的毒性和神经副作用。