Resource for Rat Genetic Models of Aerobic Capacity

大鼠有氧能力遗传模型资源

• 批准号: 8999298
• 负责人: STEVEN Loyal BRITTON
• 金额: $ 53.24万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-18 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8999298
• 关键词: Aerobic; Alzheimer' s Disease; Applied Research; Biological Models; Biomedical Research; Chromosome Mapping; Complex; Cryopreservation; DNA; Disease; Embryo; Energy Metabolism; Event; Exercise; Fatty Liver; Founder Generation; Funding; Funding Opportunities; Generations; Genetic Models; Genetic Recombination; Genotype; Goals; Grant; Health; Impaired cognition; Institution; Investigation; Link; Longevity; Metabolic syndrome; Modeling; Morbidity - disease rate; Obesity; Paper; Phenotype; Postoperative Period; Probability; Publishing; Rattus; Research Personnel; Resistance; Resolution; Resources; Risk; Running; Source; Testing; Tissues; United States National Institutes of Health; base; disorder risk; electronic data; improved; mortality

 DESCRIPTION (provided by applicant): Our goal is to provide investigators a unique rat model system and bioanylates to explore the mechanistic basis of complex diseases. The strong link between low exercise capacity and increased morbidity and mortality suggests that: aerobic energy metabolism is a central mechanistic determinant of the divide between disease and health (Aerobic Hypothesis). As an unbiased test of this hypothesis we applied divergent artificial selection for intrinsic low and high endurance treadmill running capacity starting with founder population of genetically heterogeneous rats (N/NIH). Selection across 35 generations produced lines of low capacity runners (LCR) and high capacity runners (HCR) that differ by ~8-fold in running capacity. As predicted by the Aerobic Hypothesis, disease risks segregated strongly with low aerobic capacity. The LCR score high on many risks including reduced longevity, metabolic syndrome, and Alzheimer's degeneration. The HCR score high for health factors such as VO2max and resistance to obesity. The LCR-HCR models fulfill the criteria for a P40 grant: A) The rats are valuable for biomedical research, but not generally available. B) There is a demonstrated need as evidenced by >400 publishing investigators, at >60 institutions, and 100 published papers. C) This resource serves the needs of multiple NIH ICs. D) The models and bioanalytes (e.g., DNA and tissues) will be made available widely. E) A high probability plan will move the resource to 100% self-sufficiency. F) A 7-part plan is established to attract high quality users. G) An advisory board will direct improvement. H) Embryo cryopreservation will serve as applied research to improve the resource. G) The resource opens new lines of investigation for understanding disease. Specific Aim 1. Continue selection of the LCR and HCR for generations 36-45 as a source of rats for users and to accumulate more recombination events that will enhance genetic mapping resolution. Specific Aim 2. Systematically establish bioanylate and electronic data resources and make these readily available. Specific Aim 3. Attract users for hypothesis-driven mechanistic study of complex diseases. As examples, we summarize three NIH funded ongoing studies: a) genotype-to-phenotype analysis, b) hepatic steatosis, and c) postoperative cognitive decline. Apparently disparate conditions segregated with selection for aerobic capacity suggesting we may discover new mechanistic commonalities underlying complex diseases.

 描述（由申请人提供）：我们的目标是为研究者提供一个独特的大鼠模型系统和生物分析物，以探索复杂疾病的机制基础。低运动能力和发病率和死亡率增加之间的密切联系表明：有氧能量代谢是疾病和健康之间的分界的中心机制决定因素（有氧假说）。作为这一假设的无偏检验，我们采用了不同的人工选择固有的低和高耐力跑步机运行能力的创始人人口的遗传异质性大鼠（N/NIH）。在35代中进行的选择产生了低容量跑步机（LCR）和高容量跑步机（HCR）的品系，它们的跑步能力相差约8倍。正如有氧假说所预测的那样，疾病风险与有氧能力低密切相关。LCR在许多风险上得分很高，包括寿命缩短，代谢综合征和阿尔茨海默氏症。HCR在VO 2 max和抵抗肥胖等健康因素方面得分较高。LCR-HCR模型符合P40资助的标准：A）大鼠对生物医学研究很有价值，但不是普遍可用的。B）有一个明确的需求，证明了超过400名出版研究人员，在超过60个机构，和100发表论文。C）此资源满足多个NIH IC的需求。D）模型和生物分析物（例如，DNA和组织）将广泛提供。E）高概率计划将使资源达到100%自给自足。F）建立了一个由7部分组成的计划，以吸引高质量的用户。（三）设立咨询委员会指导改进工作。H）胚胎冷冻保存将作为应用研究，以改善资源。该资源为了解疾病开辟了新的调查路线。具体目标1.继续选择第36-45代的LCR和HCR作为用户的大鼠来源，并积累更多的重组事件，这将提高遗传图谱的分辨率。具体目标2。系统地建立生物分析和电子数据资源，并使这些资源随时可用。具体目标3。吸引用户对复杂疾病进行假设驱动的机制研究。作为例子，我们总结了三个NIH资助的正在进行的研究：a）基因型-表型分析，B）肝脂肪变性，和c）术后认知功能下降。显然，不同的条件与有氧能力的选择分离，这表明我们可能会发现复杂疾病的新机制共性。