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.
Obesity significantly increases the risk for specific cancers, although the mechanisms involved are not well defined. We hypothesize that increased mutagenesis/carcinogenesis in obesity has a significant contribution due to the accumulation of genotoxic DNA-AGEs, formed as a consequence of hyperglycemia in conjuction with significant attenuation of DNA repair capacity resulting from metabolic disease. The animal models of obesity/diabetes we will use in this investigation will clarify the role of DNA-AGEs and DNA repair mechanisms in mutagenesis that should lead to direct relevance to human health by directing new diagnostic and therapeutic approaches to obesity-related cancers.
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