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).

该提议基于以下前提：氧气自由基参与线粒体衰老和转弯，整个生物体的衰老。线粒体产生的超氧化物自由基可能导致大分子并导致线粒体缺陷。这个过程最终导致衰老和生物体的灭亡。我们假设可以保护线粒体的因素自由基损害具有维持能量产生和组织功能的可能性，最终延迟衰老的发作并延长生物体的IIFESPAN。 MNSOD缺陷小鼠（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，和早期的灭亡。我们已经表明，遗传修饰符在确定中起着重要作用 SOD2 - / - 小鼠的预期寿命。因此，在长寿命的遗传背景上的SOD2 - / - 小鼠具有寿命5 在短寿命背景下比突变小鼠的时间长。我们指定了遗传修饰符 Kolegs（淘汰寿命延长的基因），并设计了一个实验的塞子来绘制Koleg Loci 并确定推定的修饰基因。迄今为止，我们已经在否则纯B6背景，将主要的Koleg映射到10厘米区域，并确定了一个推定的在含科尔的区域中的修饰基因。修饰符基因编码烟酰胺核苷酸经氢化酶（NNT），它是位于膜结合的蛋白 tfitochondria。以我们目前的发现为基础，并最终确定能够 “在线粒体抗氧化应激的抗性和延长突变体的寿命为以及野生型小鼠，提出了以下特定目标。目标1：识别其他修饰符基因通过精细映射和功能注释。目标2：NNT作为遗传的机械分析 SOD2 - / - 的修饰符。目标3：验证NNT作为寿命保证基因（滞后）。