(PQA2) Impact of obesity on endogenous mutational hotspots

(PQA2) 肥胖对内源突变热点的影响

基本信息

批准号：
8687142
负责人：
John DiGiovanni
金额：
$ 20.16万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8687142
关键词：
Acute Adopted Affect Animals B-Cell Lymphomas B-DNA Brain Burkitt Lymphoma Caloric Restriction Cancer Etiology Chromosome Breakage DNA DNA Damage DNA Double Strand Break DNA Maintenance DNA Repair DNA Repair Pathway DNA Sequence DNA Sequence Rearrangement DNA Structure DNA strand break Development Diet Double Strand Break Repair Event G-Quartets Genetic Genome Genome Stability Genomic Instability Goals Guanine H-DNA Human Human Genome Knowledge Lead Life Liver MYC gene Malignant Neoplasms Mammalian Cell Mus Mutagenesis Mutation Nonhomologous DNA End Joining Obesity Obesity associated cancer Oxidative Stress Pathway interactions Play Positioning Attribute Predisposition Prevention Process Public Health Reactive Oxygen Species Refractory Reporter Research Risk Risk Factors Role Running Skin Structure Testing Time Tissues Translocation Breakpoint Woman Work cancer risk cancer type energy balance leukemia/lymphoma mammalian genome men mouse model novel novel strategies oxidative DNA damage prevent public health relevance repaired research study response

Acute Adopted Affect Animals B-Cell Lymphomas B-DNA Brain Burkitt Lymphoma Caloric Restriction Cancer Etiology Chromosome Breakage DNA DNA Damage DNA Double Strand Break DNA Maintenance DNA Repair DNA Repair Pathway DNA Sequence DNA Sequence Rearrangement DNA Structure DNA strand break Development Diet Double Strand Break Repair Event G-Quartets Genetic Genome Genome Stability Genomic Instability Goals Guanine H-DNA Human Human Genome Knowledge Lead Life Liver MYC gene Malignant Neoplasms Mammalian Cell Mus Mutagenesis Mutation Nonhomologous DNA End Joining Obesity Obesity associated cancer Oxidative Stress Pathway interactions Play Positioning Attribute Predisposition Prevention Process Public Health Reactive Oxygen Species Refractory Reporter Research Risk Risk Factors Role Running Skin Structure Testing Time Tissues Translocation Breakpoint Woman Work cancer risk cancer type energy balance leukemia/lymphoma mammalian genome men mouse model novel novel strategies oxidative DNA damage prevent public health relevance repaired research study response

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项目摘要

DESCRIPTION (provided by applicant): The overall objective of this proposal is to understand how dietary energy balance and especially obesity influences genome stability at endogenous mutational "hotspots". To achieve this objective, we will use a novel mouse model to determine the impact of obesity on DNA structure-induced mutagenesis in various tissues from these mice. Repetitive DNA sequences are widely dispersed throughout mammalian genomes and can adopt alternative (non-B DNA) secondary structures, such as H-DNA. Importantly, these non-B DNA structure- forming sequences often co-localize with endogenous mutational "hotspots" in the human genome, implicating them in cancer etiology. For example H-DNA-forming sequences in the c-MYC gene are found at translocation breakage "hotspots" in Burkitt's lymphoma and acute B-cell lymphoma. We have developed novel mutation- reporter mice containing a human H-DNA-forming c-MYC sequence that co-localizes with a translocation breakpoint "hotspot" in Burkitt's lymphoma, and demonstrated for the first time that these sequences are mutagenic in living animals. Obesity is known to increase cellular oxidative stress and oxidative DNA damage, whereas calorie restriction has been shown to decrease cellular oxidative stress, oxidative DNA damage, reduce mutagenesis and to enhance DNA repair pathways. In addition, obesity is an important risk factor for a significant number of cancers in both men and women, including leukemias and lymphomas. However, the extent to which dietary energy balance and especially obesity influences DNA structure-induced genetic instability is not known. Thus, a goal of the proposed work is to fill this gap in knowledge. In ths proposal, we will test the working hypothesis that obesity increases DNA structure-induced genetic instability. We will examine the impact of diet-induced obesity (DIO) on DNA structure-induced mutagenesis in our novel mutation reporter mice. Several different tissues will be evaluated from these mice to determine whether there are any tissue specific differences in response to DIO. We will also explore potential mechanisms for any observed effects of obesity on DNA structure-induced genetic instability. We will focus our studies on the impact of obesity on DNA repair mechanisms as several recent studies have suggested that obesity impairs multiple DNA repair pathways, including non-homologous end-joining, a repair pathway that we have found to play a role in the processing of H-DNA structures in mammalian cells. Completion of the proposed studies will lead to a greater understanding of how obesity influences cancer development. In addition, this work will lead to the identification of novel targets for the prevention and/or treatment of obesity-related cancers.

描述（由申请人提供）：该提案的总体目的是了解饮食能量平衡，尤其是肥胖如何影响内源性突变“热点”的基因组稳定性。为了实现这一目标，我们将使用一种新型的小鼠模型来确定肥胖对这些小鼠各种组织中DNA结构诱导的诱变的影响。重复的DNA序列被广泛分散在整个哺乳动物基因组中，并且可以采用替代性（非B DNA）二级结构，例如H-DNA。重要的是，这些非B DNA结构形成序列通常与人类基因组中的内源性突变“热点”共定位，这意味着它们参与癌症的病因。例如，在伯基特淋巴瘤和急性B细胞淋巴瘤中，在C-MYC基因中的H-DNA形成序列在易位断裂“热点”中发现。我们已经开发了包含人类H-DNA成型C-MYC序列的新型突变记者小鼠，该序列与伯基特淋巴瘤中的易位断点“热点”共定位，并首次证明了这些序列在活动物中是刺激性的。已知肥胖会增加细胞氧化应激和氧化性DNA损伤，而卡路里限制已显示可减少细胞氧化应激，氧化DNA损伤，减少诱变并增强DNA修复途径。此外，肥胖是男性和女性中大量癌症（包括白血病和淋巴瘤）的重要危险因素。但是，尚不清楚饮食能量平衡，尤其是肥胖影响DNA结构引起的遗传不稳定性的程度。因此，拟议工作的目标是填补知识的差距。在THS提案中，我们将测试肥胖症增加DNA结构引起的遗传不稳定性的工作假设。我们将研究饮食诱导的肥胖症（DIO）对我们新型突变报告小鼠中DNA结构诱导的诱变的影响。将从这些小鼠中评估几种不同的组织，以确定是否有任何组织特异性差异。我们还将探索肥胖对DNA结构引起的遗传不稳定性的任何影响的潜在机制。我们将重点关注肥胖对DNA修复机制的影响，因为最近的一些研究表明，肥胖会损害多个DNA修复途径，包括非同源性最终结合，这是我们发现在哺乳动物细胞中H-DNA结构的加工中起作用的修复途径。拟议研究的完成将导致对肥胖如何影响癌症的发展有更多了解。此外，这项工作将导致对预防和/或治疗与肥胖相关的癌症的新靶标识别。