Resource for Rat Genetic Models of Aerobic Capacity

大鼠有氧能力遗传模型资源

• 批准号: 9274364
• 负责人: Lauren Gerard Koch
• 金额: $ 7.19万
• 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 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9274364
• 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 Enhancement; 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; data resource; 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（由适用提供）：我们的目标是为研究人员提供独特的大鼠模型系统和生物烷基化，以探索复杂疾病的机械基础。低运动能力与发病率和死亡率增加之间的牢固联系表明：有氧能量代谢是疾病与健康之间鸿沟的核心机械决定因素（有氧假设）。作为对该假设的无偏检验，我们将不同的人工选择应用于内在的低耐力跑步机能力，从遗传性异构大鼠（N/NIH）的创始人群开始。在35代人中的选择产生了低容量跑步者（LCR）和高容量跑步者（HCR）的线路，其跑步能力差异约为8倍。正如有氧假说所预测的那样，疾病的风险以低氧能力强烈隔离。 LCR得分高于许多风险，包括寿命降低，代谢综合征和阿尔茨海默氏症的变性。 HCR得分很高，例如vo2max和对肥胖症的耐药性。 LCR-HCR模型符合P40赠款的标准：a）大鼠对于生物医学研究很有价值，但通常不可用。 b）> 400名出版研究人员，> 60个机构和100篇已发表的论文所证明的有必要证明。 c）此资源满足了多个NIH IC的需求。 d）模型和生物分析（例如，DNA和组织）将被广泛提供。 e）高概率计划将使资源提高到100％的自给自足。 f）制定了7部分计​​划，以吸引高质量的用户。 g）顾问委员会将指导改进。 h）胚胎冷冻保存将作为应用研究以改善资源的应用。 g）资源为理解疾病开辟了新的投资线。具体目标1。继续选择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，以增强遗传映射分辨率。具体目的2。系统地建立生物烷基化和电子数据资源，并使这些资源很容易获得。特定目标3。吸引用户进行假设驱动的复杂疾病的机械研究。作为示例，我们总结了三项基于NIH的正在进行的研究：a）基因型至透明型分析，b）肝脂肪变性，c）术后认知下降。显然，有氧能力的选择隔离了不同的条件，这表明我们可能会发现复杂疾病的新机械共同点。