DNA Repair Deficiency Associated with Obesity and the Meatbolic Syndrome

据估计，日益流行的人类肥胖目前影响着超过6500万美国成年人，其中 次要后果包括但不限于，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。大多数人 在肥胖人口总数(4500万美国人)中，至少有四种以上的疾病 (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，但已经用遗传学方法进行了研究 模型和/或暴露在外源压力条件下。虽然野生型细胞保持整体能量 通过最大限度地减少暴露在活性氧物种(ROS)中对细胞的损害，疾病可以 由导致高水平ROS的各种条件启动。DMA是主要的目标之一 ROS诱导的损伤以及DNA修复缺陷与代谢的可能相互关系 对该综合征的研究尚未深入。然而，我们最近证明，携带A基因的小鼠 DNA糖基酶NEIL1缺失，出现与代谢综合征一致的症状：严重 肥胖、脂肪肝、血脂异常和胰岛素抵抗。疾病主要表现为男性基因敲除 并在与C57BL/6和杂合子广泛回交的小鼠中观察到。我们的中央 一种假说来理解修复氧化应激诱导的酶的损失之间的关系 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中含有显著升高的 未修复的损坏和删除。为了弄清NEIL1在细胞中的作用，对存活的调节， 突变和线粒体！函数将被求值。此外，由于它在维护 线粒体DNA完整性，AIMS旨在确定线粒体的身份和作用-与 核靶向形式的酶。由于初步数据显示，一些人类多态变体 的NEIL1是催化不活性的，这些变体的特征是它们启动碱基的能力 Neim缺陷小鼠的切除修复和逆转表型的能力。

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.