Hyperglycemia-induced DNA damage as a driver of genomic instability

高血糖诱导的 DNA 损伤是基因组不稳定的驱动因素

基本信息

批准号：
8795311
负责人：
TIMOTHY R O'CONNOR
金额：
$ 6.14万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8795311
关键词：
Accounting Advanced Glycosylation End Products Aldehydes Animal Model Attenuated Biochemical Biopolymers Breast Cells Cervix Uteri Chemicals Colon Carcinoma Confusion DNA DNA Adducts DNA Damage DNA Repair Data Deoxyguanosine Development Diabetes Mellitus Diabetic mouse Disease Endocrine Endometrium Epidemiologic Studies Event Excision Genomic Instability Glucose Goals Guanine Health Homeostasis Human Hyperglycemia Hyperlipidemia In Vitro Incidence Individual Induced Mutation Insulin Resistance Investigation Kidney Kinetics Knowledge Lead Link Lipids Literature Liver Malignant Neoplasms Measures Metabolic Diseases Metabolic syndrome Methods Modeling Modification Molecular Mus Mutagenesis Mutation Mutation Spectra Non-Insulin-Dependent Diabetes Mellitus Nucleosides Nucleotide Excision Repair Obese Mice Obesity Obesity associated cancer Organ Pancreas Pathologic Pathology Pathway interactions Pattern Polymers Population Predisposition Proteins Protocols documentation Publishing Reaction Relative (related person)Research Risk Role Series Signal Transduction Staging Stress Structure Testing Time Tissues Variant adduct attenuation blood glucose regulation cancer risk carcinogenesis cell growth chemical stability density design diabetic human tissue in vivo innovation mouse model multidisciplinary novel novel diagnostics novel therapeutic intervention programs repaired therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Obesity endgenders a wide spectrum of interrelated pathologies including hyperglycemia, insulin resistance, hyperlipidemia, and Type 2 diabetes, collectively termed the metabolic syndrome. This condition significantly increases risk for cancers of the colon, liver, pancreas, kidney, breast, cervix, and endometrium; however, the mechanisms responsible remain unknown. Many pathological complications of obesity and Type 2 diabetes arise from hyperglycemia and the subsequent accumulation of advanced glycation end products (AGEs) resulting from reactions of glucose-derived ?-oxo aldehydes with proteins, lipids, and DNA. Although the pathological consequences of protein-AGEs in metabolic disease have been recognized for many years, the extent of DNA-AGE accumulation and its potential role in obese/diabetic pathology are largely unexplored. Using a highly sensitive and determinative mass spectrometric method, we have shown that a major DNA-AGE, CEdG, is present at significant levels in human tissue, and its levels are substantially elevated in animl models of metabolic syndrome relative to lean euglycemic controls. We recently showed that CEdG is mutagenic in human cells, and that nucleotide excision repair (NER) is the major pathway for minimizing DNA-AGE induced genomic instability. Because NER is downregulated as consequence of adiposity and diabetes we theorize that the accumulation of mutagenic DNA-AGEs in individuals with metabolic syndrome substantially elevates their cancer susceptibility. Our long term goal is to determine how elevated DNA-AGE levels in metabolic disease contribute to genomic instability and increased vulnerability to cancer. We will test the hypothesis that hyperglycemia-induced accumulation of mutagenic DNA-AGEs in conjunction with attenuated DNA repair propels genomic instability and substantially increases cancer susceptibility. We propose that tissue-specific variations in DNA-AGE accumulation and mutagenesis account in part for the restricted range of cancers associated with obesity. Progress toward our long term goal requires elucidating the structures and chemical stabilities of the major DNA-AGEs in order to identify products most likely to contribute to genomic instability in vivo (Aim 1). To study the genotoxic pathology of DNA-AGEs in obesity, we will generate animal models of metabolic syndrome and measure tissue-specific mutations and DNA-AGE levels as a function of NER status (Aim 2). To more quantitatively define the decline in DNA repair capacity due to metabolic disease, we will measure the repair kinetics of DNA-AGEs using extracts prepared from obese/diabetic mice at progressive stages of disease (Aim 3). Successful implementation of these Specific Aims will contribute greatly toward our understanding of this link between cancer and a molecular change induced by a pathologic consequence of obesity. Moreover, we anticipate that enhancing our knowledge of hyperglycemia-induced DNA-AGE pathology will have a significant overall impact on human health and stimulate the development of novel treatments to reduce the risk of specific cancers associated with obesity.

描述（由申请人提供）：肥胖会导致一系列相互关联的病理，包括高血糖、胰岛素抵抗、高脂血症和 2 型糖尿病，统称为代谢综合征。这种情况会显着增加患结肠癌、肝癌、胰腺癌、肾癌、乳腺癌、子宫颈癌和子宫内膜癌的风险；然而，造成这种现象的机制仍然未知。肥胖和2型糖尿病的许多病理并发症起因于高血糖以及随后由葡萄糖衍生的α-氧醛与蛋白质、脂质和DNA反应导致的晚期糖基化终产物(AGE)的积累。尽管蛋白质-AGE 在代谢疾病中的病理后果已被认识多年，但 DNA-AGE 积累的程度及其在肥胖/糖尿病病理学中的潜在作用在很大程度上尚未被探索。使用高灵敏度和测定质谱方法，我们已经表明，主要的DNA-AGE，CEdG，在人体组织中以显着水平存在，并且相对于瘦的正常血糖对照，其水平在代谢综合征的动物模型中显着升高。我们最近表明，CEdG 在人类细胞中具有诱变性，而核苷酸切除修复 (NER) 是最大限度减少 DNA-AGE 诱导的基因组不稳定性的主要途径。由于肥胖和糖尿病导致 NER 下调，我们推测代谢综合征患者中突变性 DNA-AGE 的积累会显着提高其癌症易感性。我们的长期目标是确定代谢疾病中 DNA-AGE 水平升高如何导致基因组不稳定和增加患癌症的可能性。我们将检验这样一个假设：高血糖诱导的诱变 DNA-AGE 积累与 DNA 修复减弱共同推动了基因组不稳定并显着增加了癌症易感性。我们认为 DNA-AGE 积累和诱变的组织特异性变异在一定程度上解释了与肥胖相关的癌症的有限范围。为了实现我们的长期目标，需要阐明主要 DNA-AGE 的结构和化学稳定性，以确定最有可能导致体内基因组不稳定的产品（目标 1）。为了研究肥胖中 DNA-AGE 的基因毒性病理学，我们将生成代谢综合征的动物模型，并测量组织特异性突变和 DNA-AGE 水平作为 NER 状态的函数（目标 2）。为了更定量地确定代谢疾病导致的 DNA 修复能力下降，我们将使用从疾病进展阶段的肥胖/糖尿病小鼠制备的提取物来测量 DNA-AGE 的修复动力学（目标 3）。这些具体目标的成功实施将极大地有助于我们理解癌症与肥胖病理后果引起的分子变化之间的联系。此外，我们预计，增强对高血糖诱导的 DNA-AGE 病理学的了解将对人类健康产生重大的整体影响，并刺激新疗法的开发，以降低与肥胖相关的特定癌症的风险。