权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Genetics Modifiers and Longevity of MnSOD Mutant Mice

MnSOD 突变小鼠的遗传修饰和寿命

基本信息

批准号：
7477669
负责人：
Ting-Ting Huang
金额：
$ 31.58万
依托单位：
PALO ALTO VETERANS INSTIT FOR RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7477669
关键词：
Aging Animal Model Binding Proteins Biological Models Birth Caenorhabditis elegans Cardiac Cell physiology Cells Citric Acid Cycle Dilated Cardiomyopathy Electron Transport Embryo Enzymes Failure Free Radicals Funding Genes Genetic Hand Hour Intervention Knock-out Lead Life Life Expectancy Longevity Manganese Superoxide Dismutase Maps Membrane Metabolic acidosis Mitochondria Mitochondrial DNA Modification Mus Mutant Strains Mice Mutation NAD(P)+ transhydrogenase Organism Oxidative Phosphorylation Oxidative Stress Phenotype Play Population Pregnancy Process Production Research Personnel Resistance Role Series Superoxides Time Tissues Transgenic Organisms Validation Variant Week Whole Organism Wild Type Mouse Work base congenic day design free radical oxygen human SOD2 protein longevity gene macromolecule mutant novel programs research study senescence

项目摘要

This proposal is based on the premise that oxygen free radicals are involved in mitochondiral aging and in turn, aging of the whole organism. Superoxide radicals generated in the mitochondda 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 iifespan of the organism. MnSOD deficient mice (Sod2-/-) represent an animal model with increased mitochonddal 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 sedes 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 Tfitochondria. To build upon our current findings and ultimately identify novel genetic modifiers capable of "nodulating 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).

这一建议是基于氧自由基参与线粒体老化和转，整个有机体的老化。线粒体中产生的超氧化物自由基可导致细胞损伤，大分子并导致线粒体缺陷。这一过程最终导致了衰老和死亡的有机体。我们假设能够保护线粒体的因子有可能维持能量产生和组织功能，并最终延缓衰老的开始并延长机体的寿命。MnSOD缺陷小鼠（Sod 2-/-）代表线粒体超氧自由基增加，组织损伤加速，和过早死亡我们已经表明，遗传修饰剂在确定 Sod 2-/-小鼠的预期寿命。因此，具有长寿遗传背景的Sod 2-/-小鼠的寿命为5 比短寿命背景下的突变小鼠长一倍。我们将基因修饰剂 KOLEG（KnockOut Life-Extensiving Genes）基因的克隆，并设计了一系列的实验来定位KOLEG基因座并鉴定推定的修饰基因。到目前为止，我们已经产生了同源KOLEG-containing小鼠在一个否则纯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含有KOLEG-containing区域。修饰基因编码烟酰胺核苷酸转氢酶（NNT），其是位于细胞内膜中的膜结合蛋白，线粒体。基于我们目前的发现，并最终确定新的遗传修饰剂， “增强线粒体对增加的氧化应激的抵抗力，延长突变体的寿命，以及野生型小鼠，提出了以下具体目标。目的1：鉴别其他改性剂基因的精细定位和功能注释。目的2：Nnt作为基因的机制分析 Sod 2-/-的修饰剂。目的3：验证Nnt作为长寿保证基因（LAG）。