A New Translational Rat Model for Evaluating Anti-Aging Interventions

用于评估抗衰老干预措施的新转化大鼠模型

• 批准号: 10665539
• 负责人: STEVEN N. AUSTAD
• 金额: $ 22.96万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10665539
• 关键词: African; Aging; Alzheimer' s Disease; Animals; Biological Assay; Biology; Blood; Breeding; Cancer Intervention; Clinic; Code; Cognitive; Data; Dose; Estradiol; Fatty Liver; Female; Functional disorder; Genes; Genetic; Genetic Variation; Genomics; Genotype; Goals; Hand Strength; Health; Human; Human Biology; Hybrids; Inbred Strain; Inbreeding; Intervention; Intervention Studies; Laboratory Rat; Life; Long-Term Effects; Longevity; Metabolic; Mitochondria; Mitochondrial Proteins; Modeling; Monkeys; Mothers; Mouse Strains; Mus; Muscle; Norway; Nuclear; Nucleotides; Obese Mice; Outcome; Pathology; Pharmaceutical Preparations; Phase; Physiological; Physiology; Plasma; Population; Process; Proteins; Rattus; Research; Research Infrastructure; Research Personnel; Ribosomes; Scheme; Sex Differences; Site; Specificity; Standardization; Stress; Supplementation; Testing; Time; Tissues; Transfer RNA; Translating; age related; anti aging; blood glucose regulation; bone; cognitive capacity; design; diet-induced obesity; endurance exercise; improved; insulin sensitivity; inter-institutional; male; metabolic abnormality assessment; mitochondrial genome; mouse model; novel; pharmacologic; programs; sex; therapy development; translation to humans

We propose to develop as sustainable aging research infrastructure, a new and unique genetically heterogeneous laboratory rat model that can be used to evaluate putative life- and health-extending interventions. The rat has numerous advantages over the mouse for interventional aging research including more human-like physiology and pathophysiology, more cognitive sophistication, and greater genetic diversity compared with standard mouse strains. Inspired by the UM-HET3 mice used by the Interventions testing program, our rat model (OKC-HETb/w) will also be populations of genetically heterogeneous F2 descendants of 4 divergent, inbred strains. A significant difference from the UM-HET3 mice, our breeding scheme takes advantage of the rat’s substantial mitochondrial genomic diversity compared with the mouse to create a population half of which carries the BN strain mitochondria (OKC-HETb), the other half carries the WKY strain mitochondria (OKC- HETw). These mitochondrial genomes mimic great human mitochondrial diversity in that they differ at 95 nucleotides involving 11 of 13 mitochondrial protein-coding genes, 5 tRNA’s and both ribosomal subunits. Our preliminary data show that the OKC-HETb and OKC-HETw rats respond differently to exercise endurance, grip strength, and responsiveness to 17α-estradiol. As a proof of principle, we will evaluate in the OKC-HETb/w rat an anti-aging intervention (17α-estradiol) that was previously found to enhance the longevity of male mice only. An intriguing outcome of our project will be to verify whether or not, this sex-specificity is also seen in our rat model. In the R21 phase of this project we will produce the OKC-HETb/w rats and (1) characterize energetics-based health assays at whole animal and cellular levels under standard and stressed (HFD) conditions in both sexes in both mitochondrial genotypes, (2) determine the dose of 17α-estradiol that will yield blood levels comparable to those found at effective life-extending doses in the ITP study and the short-term effects of 17α-estradiol on metabolic parameters in diet-induced obese mice of both sexes, and (3) provide investigators with tissues as well as young and old OKC-HETb/w. In the R33 phase, we will use the information gained in the R21 phase to: (1) determine the effect of 17α-estradiol on the longevity and age-related pathology in both sexes and both mitochondrial genotypes and (2) determine the long-term effects of 17α-estradiol on age-related changes in metabolic and health parameters, again, in both sexes and both mitochondrial genotypes.

我们建议开发一种新的、独特的遗传基因作为可持续老龄化研究基础设施 可用于评估假定的生命和健康延长的异质实验室大鼠模型 干预措施。在介入衰老研究中，大鼠比小鼠具有许多优势，包括更多 类似人类的生理学和病理生理学、更复杂的认知和更大的遗传多样性 与标准小鼠品系相比。受到干预测试中使用的 UM-HET3 小鼠的启发 计划中，我们的大鼠模型 (OKC-HETb/w) 也将是 4 个基因异质 F2 后代的群体 发散的近交系。与 UM-HET3 小鼠的显着差异，我们的育种方案利用了优势 与小鼠相比，大鼠的线粒体基因组多样性显着增加，从而产生了一半的种群 一半携带BN株线粒体（OKC-HETb），另一半携带WKY株线粒体（OKC- HETw）。这些线粒体基因组模仿了人类线粒体的巨大多样性，因为它们的差异有 95 涉及 13 个线粒体蛋白编码基因中的 11 个、5 个 tRNA 和两个核糖体亚基的核苷酸。我们的 初步数据显示，OKC-HETb 和 OKC-HETw 大鼠对运动耐力、握力的反应不同 强度和对 17α-雌二醇的反应性。作为原则证明，我们将在 OKC-HETb/w 大鼠中评估 抗衰老干预（17α-雌二醇）此前被发现只能延长雄性小鼠的寿命。一个 我们项目的有趣结果将是验证这种性别特异性是否也出现在我们的大鼠模型中。 在该项目的 R21 阶段，我们将生产 OKC-HETb/w 大鼠，并且 (1) 表征基于能量的 在标准和应激 (HFD) 条件下对两性进行整体动物和细胞水平的健康检测 在两种线粒体基因型中，(2) 确定 17α-雌二醇的剂量，该剂量将产生可比的血液水平 ITP 研究中发现的有效延长生命剂量的药物以及 17α-雌二醇对 饮食诱导的两性肥胖小鼠的代谢参数，以及（3）为研究人员提供组织 以及年轻和年长的 OKC-HETb/w。在R33阶段，我们将使用R21阶段获得的信息来： (1) 确定 17α-雌二醇对两性和男女的寿命和年龄相关病理的影响 线粒体基因型和（2）确定 17α-雌二醇对年龄相关变化的长期影响 代谢和健康参数同样适用于两种性别和两种线粒体基因型。