Genetics Modifiers and Longevity of MnSOD Mutant Mice

MnSOD 突变小鼠的遗传修饰和寿命

• 批准号: 7095897
• 负责人: Ting-Ting Huang
• 金额: $ 30.89万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7095897
• 关键词: Caenorhabditis elegans; NAD(P) transhydrogenase; animal genetic material tag; biological models; cell growth regulation; cell senescence; cytoprotection; embryo /fetus; embryogenesis; gene interaction; genetic mapping; genetic polymorphism; genetic regulation; genetically modified animals; helminth genetics; laboratory mouse; longevity; mitochondria; oxidative stress; protein structure function; superoxide dismutase; superoxides

DESCRIPTION (provided by applicant): This proposal is based on the premise that oxygen free radicals are involved in mitochondrial aging and in turn, aging of the whole organism. Superoxide radicals generated in the mitochondria can lead to damage of macromolecules and result in defective mitochondria. This process ultimately leads to the state of senescence and the demise of the organism. We hypothesize that factors that can protect the mitochondria from free radical damage have the potential to maintain energy production and tissue function, and ultimately to delay the onset of senescence and prolong the lifespan of the organism. MnSOD deficient mice (Sod2-/-) represent an animal model with increased mitochondrial superoxide radicals, accelerated tissue damage, and early demise. We have showed that genetic modifiers play an important role in the determination of the life expectancy of Sod2-/- mice. Thus, Sod2-/- mice on a long-lived genetic background have a lifespan 5 times longer than that of the mutant mice on a short-lived background. We designated the genetic modifiers KOLEGs (KnockOut Life-Extending Genes) and designed a series of experiments to map the KOLEG loci and to identify putative modifier genes. To date, we have generated congenic KOLEG-containing mice on an otherwise pure B6 background, mapped the major KOLEG to a 10 cM region, and identified a putative modifier gene in the KOLEG-containing region. The modifier gene encodes the nicotinamide nucleotide transhydrogenase (NNT), which is a membrane-bound protein located in the inner membrane of the mitochondria. To build upon our current findings and ultimately identify novel genetic modifiers capable of "modulating mitochondrial resistance to increased oxidative stress and extending the lifespans of mutant as well as wild type mice, the following specific aims are proposed. Aim 1: Identification of additional modifier genes by fine mapping and functional annotation. Aim 2: Mechanistic analysis of Nnt as the genetic modifier of Sod2-/-. Aim 3: Validation of Nnt as a longevity assurance gene (LAG).

描述（由申请人提供）：该提案基于以下前提：氧气自由基参与线粒体衰老，而整个生物体的衰老又涉及。线粒体中产生的超氧化物自由基会导致大分子的损伤并导致线粒体缺陷。这个过程最终导致衰老状态和生物体的灭亡。我们假设可以保护线粒体免受自由基损伤的因素有可能维持能量产生和组织功能，并最终延迟衰老的发作并延长生物体的寿命。 MNSOD缺乏小鼠（SOD2 - / - ）代表一种动物模型，其线粒体超氧化物自由基，加速组织损伤和早期灭亡。我们已经表明，遗传修饰剂在确定SOD2 - / - 小鼠的预期寿命中起着重要作用。因此，在长寿命遗传背景上的SOD2 - / - 小鼠的寿命比短寿命背景的突变小鼠长5倍。我们指定了遗传修饰剂Kolegs（基因敲除生命的基因），并设计了一系列实验来绘制Koleg基因座并识别推定的修饰剂基因。迄今为止，我们已经在原本纯的B6背景上生成了含有Koleg的先天小鼠，将主要的Koleg映射到10 cm区域，并在含Koleg的区域中确定了一个假定的修饰剂基因。修饰剂基因编码烟酰胺核苷酸经氢化酶（NNT），该酶是一种位于线粒体内膜中的膜结合蛋白。为了建立我们当前的发现并最终确定能够“调节线粒体耐药性增加氧化压力并延长突变体和野生型小鼠的寿命，提出了以下特定目的，提出了以下特定目的1：通过细微的映射和功能分析nnt nnd sod-sodififs-nter-sectififs-nnd，提出了以下特定目的。 NNT是长寿保证基因（滞后）。