Long-lived mice and species as test beds for drug and pathway discovery

长寿小鼠和物种作为药物和途径发现的试验台

• 批准号: 10210339
• 负责人: RICHARD A MILLER
• 金额: $ 52.07万
• 依托单位: CALIFORNIA PACIFIC MED CTR RES INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10210339
• 关键词: Acarbose; Adult; Aging; Aorta; Beds; Biological Markers; Biology of Aging; Birds; Brain; Caloric Restriction; Cell Line; Cells; Characteristics; Collaborations; Collection; Data; Data Set; Databases; Diet; Disease; Dwarfism; Elderly; Estradiol; Evolution; Exposure to; Fatty acid glycerol esters; Fibroblasts; Genes; Growth Hormone Receptor; Health; Heart; Human; Inherited; Interferons; Intervention; Kinetics; Knock-out; Laboratories; Libraries; Liver; Longevity; Mammals; Messenger RNA; Methods; Mitochondria; Mus; Muscle; Mutation; Organ; Oxidation-Reduction; Pathway interactions; Pattern; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Primates; Property; Protein Analysis; Proteins; Proteomics; Protocols documentation; Publishing; Regulation; Resistance; Resources; Rodent; Sampling; Serum; Sirolimus; Source; Stress; Systems Biology; Testing; Tissues; Treatment Protocols; Trees; Work; age effect; age related; base; biological adaptation to stress; cheminformatics; data integration; differential expression; drug candidate; drug testing; healthy aging; interest; metabolomics; mouse model; mutant; novel; protein metabolite; success; targeted biomarker; thioredoxin reductase 2; trait; transcriptome sequencing

The experimental plans focus on two central themes: (a) that comparison of properties of cell lines from long- and short-lived species can suggest hypotheses about pathways that modulate the pace of aging, and (b) that availability of multiple mouse models for delayed aging can test ideas about factors that are indicative of, and in some cases causally connected to, the biology of aging and late-life disease. Aim 1 will evaluate metabolomic and peptide signatures ("analytes") from cell lines of rodents, birds, and primates varying in lifespan from 4 to 70 years, to see which analyte signatures are shared among evolutionary clades and are thus likely to be required for evolution of longevity. Aim 2 will develop analyte signatures from plasma and internal tissues of six varieties of slow-aging mice (three drugs, one diet, and two mutations). We predict we will find overlapping signatures in these long-lived mice, suggesting "common pathways" associated with healthy longevity regardless of the mode of lifespan extension. We predict that some of these biomarkers will also be seen in plasma from exceptionally healthy, long-lived people. We also predict that analytes and signatures found in the cross-species comparisons of Aim 1 will be detectable in slow-aging mice as well. Aim 3 focuses on a collaboration with the Cheminformatics Core, to test sets of drugs in cell lines and in mice. The hypothesis is that the Core-nominated drugs will render mouse and human cells resistant to multiple stresses, and will modify analyte profiles in mice to resemble those of slow-aging mice and long-lived humans. Endpoints for the drug treatment protocols, in cells and mice, will also include those we have previously shown to be characteristic of cells from long-lived species and organs of long-lived mice, including PSMB8, IFN R2- responsive mRNAs, and mitochondrial TXNRD2. We will make extensive use of collaborations with the Consortium's projects on metabolomics and proteomics, and the Cheminformatics Core, and our data will be a rich source of information for the Schork project and the systems biology core as well. We hope to show that analyses of species-specific cellular traits, and materials from slow-aging mice, can greatly enrich the search for pathways, genes, and drugs of special interest for protection of people from the effects of aging and age- dependent diseases.

实验计划集中在两个中心主题：（a）比较来自长时间的细胞系的特性， 和寿命短的物种可以提出有关调节衰老速度的途径的假设，以及（B） 延迟衰老的多种小鼠模型的可用性可以测试有关指示性因素的想法， 在某些情况下与衰老和老年疾病的生物学有因果关系。目标1将评估 来自啮齿动物、鸟类和灵长类动物的细胞系的代谢组学和肽特征（“分析物”）， 寿命从4年到70年，以查看哪些分析物签名在进化分支之间共享， 因此可能是长寿进化所必需的。目标2将从血浆中开发分析物特征， 六种缓慢衰老小鼠的内部组织（三种药物，一种饮食和两种突变）。我们预测， 将在这些长寿小鼠中发现重叠的特征，这表明与以下相关的“共同途径”： 健康长寿，无论寿命延长的模式。我们预测，这些生物标志物中的一些将 也可以在非常健康长寿的人的血浆中看到。我们还预测，分析物和 在Aim 1的跨物种比较中发现的特征也可以在缓慢衰老的小鼠中检测到。目的 3侧重于与化学信息学核心的合作，在细胞系和小鼠中测试药物组。的 一种假设是，核心提名的药物将使小鼠和人类细胞对多种应激具有抗性， 并将修改小鼠中的分析物分布，使其类似于缓慢衰老小鼠和长寿人类的分析物分布。 在细胞和小鼠中，药物治疗方案的终点也将包括我们先前展示的那些终点 是来自长寿物种和长寿小鼠器官的细胞的特征，包括PSMB 8、IFN R2- 响应mRNA和线粒体TXNRD 2。我们将广泛利用与 联盟的代谢组学和蛋白质组学项目，以及化学信息学核心，我们的数据将是一个 Schork项目和系统生物学核心的丰富信息来源。我们希望能证明 对物种特异性细胞特征的分析，以及来自缓慢衰老小鼠的材料，可以极大地丰富搜索 对于保护人们免受衰老和年龄影响的途径，基因和药物具有特殊意义- 依赖性疾病。