DNA Repair Deficiency Associated with Obesity and the Meatbolic Syndrome

目前，据估计，人类肥胖症的日益流行影响了超过6500万的美国成年人， 继发性后果，包括但不限于寿命缩短、非酒精性脂肪肝 疾病、心血管疾病增加、中风和2型糖尿病发病率增加。大多数 总肥胖人口（> 4500万美国人）中有至少四种以上疾病的组合 （肥胖、胰岛素抵抗、血脂异常和高血压），统称为代谢综合征。 这些疾病的根本原因还没有很好地确定，但已经使用遗传学方法进行了研究。 模型和/或暴露于外源性应激条件。虽然野生型细胞保持整体能量 通过使暴露于活性氧（ROS）的细胞损伤最小化，疾病可以 由导致高水平ROS的各种条件引发。DMA是一个主要的目标， ROS诱导的损伤，以及缺陷DNA修复和代谢之间可能的相互关系 综合征尚未深入探讨。然而，我们最近证明，携带一种 DNA糖基化酶NEIL 1缺失，出现与代谢综合征一致的症状：重度 肥胖、脂肪肝、血脂异常和胰岛素抵抗。疾病主要表现在男性基因敲除 在与C57 BL/6和杂合子广泛回交的小鼠中观察到。我们的中央 这一假说旨在了解修复氧化应激诱导的酶的损失与 DNA损伤和代谢综合征的发展是，在这些动物中， 启动导致代谢综合征的事件所需的DNA损伤阈值显著降低。 支持这一模型的证据是线粒体！DNA中含有大量的 未修复的损坏和删除。为了辨别NEIL 1在细胞中的作用，存活的调节， 突变和线粒体功能将被评估。此外，由于其在维护 线粒体DNA完整性，目的是确定线粒体的身份和作用-与 酶的核靶向形式。由于初步数据显示，一些人类多态性变体 的NEIL 1是催化失活的，这些变体将表征其引发碱基转移的能力。 切除修复和逆转neiM缺陷小鼠表型的能力。

The growing epidemic of human obesity is currently estimated to affect over 65 million adult Americans, with secondary consequences including but not limited to, decreased life span, non-alcohol-induced fatty liver disease, increased cardiovascular disease, increased incidence of stroke and type 2 diabetes. The majority of the total obese population (> 45 million Americans) has a combination of at least four of these disorders (obesity, insulin resistance, dyslipidemia, and hypertension), collectively known as the Metabolic Syndrome. The underlying causes of these diseases are not well established, but have been investigated using genetic models and/or exposure to conditions of exogenous stress. Although wild-type cells maintain overall energy homeostasis by minimizing cellular damage from exposure to reactive oxygen species (ROS), disease can be initiated by a variety of conditions that result in high levels of ROS. DMA is one of the major targets of ROS-induced damage, and the possible interrelationship between defective DNA repair and Metabolic Syndrome has not been explored in depth. However, we recently demonstrated that mice carrying a deletion of the DNA glycosylase NEIL1, develop symptoms consistent with Metabolic Syndrome: severe obesity, fatty liver, dyslipidemia, and insulin resistance. Disease is manifested primarily in male knockout mice and is observed in mice extensively backcrossed to C57BL/6 and heterozygotes. Our central hypothesis to understand the relationship between the loss of an enzyme that repairs oxidative-stressinduced DNA damage and the development of the Metabolic Syndrome is that in these animals, the threshold of DNA damage required to initiate events leading to Metabolic Syndrome is significantly reduced. Evidence supporting this model is that mitochondria! DNA contains significantly elevated levels of unrepaired damage and deletions. To discern the role that NEIL1 plays in cells, modulation of survival, mutagenesis and mitochondria! function will be evaluated. Additionally, due to its central role in maintaining mtDNA integrity, aims are designed to determine the identity and role of the mitochondrial- versus the nuclear-targeted forms of the enzyme. Since preliminary data show that some human polymorphic variants of NEIL1 are catalytically inactive, these variants will be characterized for their ability to initiate base excision repair and the ability to reverse the phenotype of the neiM -deficient mice.