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：
8719437
负责人：
TIMOTHY R O'CONNOR
金额：
$ 4.22万
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/8719437
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）：肥胖最终末端各种相互关联的病理，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。这种情况大大增加了结肠，肝脏，胰腺，肾脏，乳房，子宫颈和子宫内膜的癌症的风险。但是，负责的机制仍然未知。肥胖和2型糖尿病的许多病理并发症是由高血糖引起的，随后由葡萄糖来源的反应？ - 氧醛与蛋白质，脂质和DNA的反应引起的晚期糖基化终产物（年龄）。尽管多年来已经识别出蛋白质年龄在代谢疾病中的病理后果，但在很大程度上尚未探索DNA-AGE积累及其在肥胖/糖尿病病理学中的潜在作用的程度。使用高度敏感的和确定性的质谱法，我们已经表明，人类组织中的主要DNA-AGE（CEDG）存在于显着水平，并且在代谢综合征的动画模型中，相对于瘦糖类控制的动画模型，其水平显着升高。我们最近表明，CEDG在人类细胞中是诱变的，核苷酸切除修复（NER）是最大程度地减少DNA-AGE诱导基因组不稳定性的主要途径。由于NER由于肥胖和糖尿病而被下调，因此我们认为，代谢综合征个体中诱变DNA-AGE的积累显着提高了其癌症的易感性。我们的长期目标是确定代谢疾病中的DNA年龄水平升高如何促进基因组不稳定性和增加对癌症的脆弱性。我们将检验以下假设：高血糖诱导的诱变DNA-AGAS与减弱的DNA修复促进了基因组不稳定性并大大提高了癌症的易感性。我们提出，与肥胖相关的癌症范围有限范围内，DNA-AGE积累和诱变的组织特异性变化。朝着我们的长期目标的进展需要阐明主要DNA-AGES的结构和化学稳定性，以便确定最有可能导致体内基因组不稳定性的产品（AIM 1）。为了研究肥胖症中DNA-AGE的遗传毒性病理，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水平与NER状态的关系（AIM 2）。为了更定量地定义由于代谢性疾病而导致的DNA修复能力下降，我们将使用从肥胖/糖尿病小鼠的疾病渐进阶段制备的提取物测量DNA-AGE的维修动力学（AIM 3）。这些特定目标的成功实施将极大地促进我们对癌症与肥胖症的病理后果引起的分子变化之间这种联系的理解。此外，我们预计，增强我们对高血糖诱导的DNA-AGE病理学的了解将对人类健康产生重大影响，并刺激新型治疗方法的发展，以降低与肥胖相关的特定癌症的风险。