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：
10369517
负责人：
STEVEN N. AUSTAD
金额：
$ 18.52万
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/10369517
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 Pharmacology Phase Physiological Physiology Plasma Population Process Proteins Rat-1 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 base blood glucose regulation bone cognitive capacity design diet-induced obesity endurance exercise improved insulin sensitivity male metabolic abnormality assessment mitochondrial genome mouse model novel 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.

我们建议发展为可持续的老化研究基础设施，这是一种新的遗传学独特的可用于评估推定的寿命和健康延伸的异质实验室大鼠模型干预措施。大鼠比鼠标具有许多优势，用于介入衰老研究，包括更多人类的生理学和病理生理学，更多的认知社会化以及更大的遗传多样性与标准小鼠菌株相比。受干预测试使用的UM-HET3小鼠的启发程序，我们的大鼠模型（OKC-HETB/W）也将是4个遗传异质F2后代的种群发散的近交菌株。与UM-HET3小鼠有显着差异，我们的育种方案利用了优势与小鼠相比，大鼠的实质性线粒体基因组多样性中有一半的人口带有BN菌株线粒体（OKC-HETB）的，另一半带有WKY菌株线粒体（OKC- hetw）。这些线粒体基因组模仿了伟大的人类线粒体多样性，因为它们在95中有所不同涉及13个线粒体蛋白编码基因，5个tRNA和两个核糖体亚基的核苷酸。我们的初步数据表明，OKC-HETB和OKC-HETW大鼠对运动耐力的反应不同，抓地力强度和对17α-雌二醇的反应性。作为原则的证明，我们将在OKC-HETB/W at an an an A 抗衰老干预（17α-雌二醇）以前发现仅增强雄性小鼠的寿命。一个我们项目的有趣结果将是验证是否在我们的大鼠模型中可以看到这种特异性。在该项目的R21阶段，我们将生产OKC-HETB/W大鼠，（1）表征基于能量的整个动物和细胞水平的健康测定在两种线粒体基因型中，（2）确定17α-雌二醇的剂量将产生可比的血液水平在ITP研究中以有效延长寿命剂量发现的那些和17α-雌二醇对的短期影响两性饮食引起的肥胖小鼠的代谢参数，（3）为研究人员提供组织以及年轻的OKC-HETB/W。在R33阶段，我们将使用在R21阶段获得的信息为：（1）确定17α-雌二醇对性别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性别和线粒体基因型的代谢和健康参数再次。