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

基本信息

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
项目类别：
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&apos 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

项目摘要

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受到干预测试中使用的 UM-HET3 小鼠的启发。计划中，大鼠我们的模型 (OKC-HETb/w) 也将是 4 的遗传异质 F2 后代群体与 UM-HET3 小鼠有显着差异，我们的育种方案利用了这一优势。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其中一半携带 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多样性，因为它们在 95 处存在差异。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。初步数据显示，OKC-HETb 和 OKC-HETw 大鼠对运动耐力、握力的反应不同作为原理证明，我们将评估 OKC-HETb/w 大鼠的强度和反应性。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。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。