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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).

这一建议的前提是氧自由基参与了线粒体的老化和反过来，整个生物体的衰老。线粒体中产生的超氧阴离子自由基可导致细胞损伤并导致线粒体有缺陷。这一过程最终导致了衰老和有机体的死亡。我们假设可以保护线粒体的因子来自自由基的损害有可能维持能量生产和组织功能，并最终延缓衰老，延长机体寿命。锰超氧化物歧化酶缺陷小鼠(Sod2-/-) 代表了一种线粒体超氧阴离子自由基增加，加速组织损伤，和早逝。我们已经证明，遗传修饰物在确定 Sod2-/-小鼠的预期寿命。因此，具有长寿遗传背景的Sod2-/-小鼠的寿命为5 比在短寿命背景下的突变小鼠长出数倍。我们把基因修饰物命名为 KOLEG(基因敲除延长寿命)，并设计了一系列实验来定位KOLEG基因座并鉴定可能的修饰基因。到目前为止，我们已经在一个含有KOLEG的同源基因小鼠其他纯的B6背景，将主要的KOLEG映射到10厘米的区域，并识别出假定的含有KOLEG区域的修饰基因。修饰基因编码烟酰胺核苷酸。转氢酶(NNT)是一种膜结合蛋白，位于细胞的内膜。特菲特萨。以我们目前的发现为基础，并最终确定能够 “提高线粒体对氧化应激的抵抗力，延长突变体AS的寿命以及野生型小鼠，提出了以下具体目标。目标1：确定附加修饰语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 Sod2的修饰符-/-。目的3：验证NNT是否为长寿保证基因(LAG)。