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（申请人提供）：该提案基于氧自由基参与线粒体衰老并进而参与整个生物体衰老的前提。线粒体内产生的超氧自由基可导致大分子物质的损伤，导致线粒体缺陷。这一过程最终导致机体的衰老和死亡。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生并延长生物体的寿命。MnSOD缺陷小鼠（Sod 2-/-）代表具有增加的线粒体超氧化物自由基、加速的组织损伤和早期死亡的动物模型。我们已经表明，遗传修饰剂在确定Sod 2-/-小鼠的预期寿命中起着重要作用。因此，具有长寿遗传背景的Sod 2-/-小鼠的寿命比具有短命背景的突变小鼠的寿命长5倍。我们指定的遗传修饰KOLEGs（敲除寿命延长基因），并设计了一系列的实验来映射KOLEG基因座，并确定假定的修饰基因。到目前为止，我们已经产生了同源KOLEG-containing小鼠，否则纯B6背景，映射的主要KOLEG到10厘米的区域，并确定了一个假定的修饰基因在KOLEG-containing区域。修饰基因编码烟酰胺核苷酸转氢酶（NNT），其是位于线粒体内膜中的膜结合蛋白。为了建立在我们目前的发现基础上，并最终确定能够“调节线粒体对增加的氧化应激的抵抗力并延长突变型和野生型小鼠的寿命”的新型遗传修饰剂，提出了以下具体目标。目的1：通过精细定位和功能注释鉴定额外的修饰基因。目的2：Nnt作为Sod 2-/-的遗传修饰剂的机制分析。目的3：验证Nnt作为长寿保证基因（LAG）。