Resource for Rat Genetic Models of Aerobic Capacity

大鼠有氧能力遗传模型资源

• 批准号: 9146432
• 负责人: STEVEN Loyal BRITTON
• 金额: $ 44.46万
• 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/9146432
• 关键词: Aerobic; Alzheimer' s Disease; Applied Research; Biological Models; Biomedical Research; Chromosome Mapping; Complex; Cryopreservation; DNA; Disease; Embryo; Energy Metabolism; Event; 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; VO2max; base; disorder risk; electronic data; exercise capacity; improved; mortality; treadmill

 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(申请人提供)：我们的目标是为研究人员提供一种独特的大鼠模型系统和生物材料，以探索复杂疾病的机制基础。低运动量与发病率和死亡率增加之间的强烈联系表明：有氧能量代谢是疾病与健康(有氧假说)之间差异的核心机械决定因素。作为对这一假设的无偏检验，我们从遗传异质性大鼠(N/NIH)的创始群体开始，对固有的低耐力和高耐力跑台跑能力进行了发散性人工选择。通过对35代人的选择，产生了低能力跑步者(LCR)和高能力跑步者(HCR)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，疾病风险与低有氧能力有很强的隔离。LCR在许多风险方面得分很高，包括寿命缩短、代谢综合征和阿尔茨海默氏症。在健康因素方面，如最大摄氧量和对肥胖的抵抗力，HCR得分很高。LCR-HCR模型符合P40资助的标准：a)大鼠对生物医学研究有价值，但不是普遍可用的。B)400名出版调查员、60家机构和100篇发表的论文证明了这一需求。C)该资源可满足多个NIH IC的需求。D)将广泛提供模型和生物分析物(例如DNA和组织)。E)高概率计划将使资源达到100%自给自足。F)制定了7部分计划以吸引高质量的用户。G)一个咨询委员会将指导改进。H)胚胎冷冻保存将作为改良资源的应用研究。G)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36-45代的LCR和Hcr作为用户的鼠源，并积累更多的重组事件，以提高遗传图谱的分辨率。具体目标2.系统地建立生物资源和电子数据资源，并使其随时可用。具体目标3.吸引用户进行复杂疾病的假说驱动的机制研究。作为例子，我们总结了三项由美国国立卫生研究院资助的正在进行的研究：a)基因-表型分析，b)肝脏脂肪变性，c)术后认知能力下降。明显不同的情况与有氧能力的选择相分离，这表明我们可能会发现复杂疾病背后的新的机械共性。