Resource for Rat Genetic Models of Aerobic Capacity

描述(由申请人提供)：基于有氧运动能力与全因发病率和死亡率之间的强烈统计关联，假设人工选择低有氧运动能力和高有氧运动能力的大鼠将产生也与疾病风险进行对比的模型。如果这是真的，这将支持这样的观点，即氧代谢受损是疾病风险的机械基础的共同特征。20代双向选拔产生了低能力跑步者(LCR)和高能力跑步者(HCR)品系，它们在有氧跑步机上的跑步能力相差超过5倍。LCR在包括代谢综合征在内的众多风险上得分很高，而HCR在健康因素(如最大耗氧量)上得分很高。重要的是，LCR还对高脂肪饮食等环境健康风险做出了更多反应。 长期目标是机械地理解区分疾病风险的这些不同模型的特征，并最终使这些模型成为经济上可行和自给自足的资源。其具体目标是：1)继续双向人工选择，直到发散高原；2)产生和表型LCR和Hcr，用于生理和疾病风险差异的机械评估；特别强调使用新的生物信息学方法评估差异基因表达；以及3)通过产生一组代表跑步能力的5倍划分的近交系来稳定模型中的基因类型。我们描述了四项正在积极进行的大规模研究作为代表性的例子：a)对LCR和HCR之间衰老和寿命的差异进行机械性评估(Russ Hepple)，b)测试非常年轻的LCR或HCR中的运动或热量限制是否对代谢终点有长期的积极“印记”效应(Charles Burant)，c)解释使用导航15个数据库的“分子概念图”生成的大量表达阵列(Arul Chinnaiyan)，以及4)探索与HCR相比，LCR中更高焦虑和抑郁的分子基础(Huda Akil)。人类种群的遗传和环境变化给复杂疾病的研究带来了相当大的困难，使动物模型成为一条有吸引力的途径。LCR和HCR是基于假设的模型，目前已知可以划分多种疾病风险，更有可能被定义。从这些模型中获得的信息将立即为更有效的复杂疾病诊断、预防和治疗模式的转化性研究提供途径。

DESCRIPTION (provided by applicant): Based upon the strong statistical association between aerobic capacity and all-cause morbidity and mortality, it was hypothesized that artificial selection of rats for low and high aerobic exercise capacity would yield models that also contrast for disease risks. If true, this would support the notion that impaired oxygen metabolism is a common feature that mechanistically underlies disease risks. Twenty generations of bidirectional selection produced lines of low capacity runners (LCR) and high capacity runners (HCR) that differ by over 5-fold in aerobic treadmill running capacity. The LCR score high on numerous risks including the metabolic syndrome and the HCR score high for health factors such as maximal oxygen consumption. Importantly, the LCR also respond more to environmental health risks such high fat diet. The long-term goals are to understand mechanistically the features that divide these contrasting models for disease risk and to ultimately make these models an economically viable and self-sustaining resource. The specific aims are to: 1) continue two-way artificial selection until divergence plateaus, 2) generate and phenotype LCR and HCR for mechanistic evaluation of physiologic and disease risk differences; special emphasis will be given to evaluation of differential gene expression using novel bioinformatics approaches, and, 3) stabilize genotypes within the models by producing a panel of inbred strains that represent the 5-fold divide for running capacity. We describe four large-scale studies that are being pursued aggressively as representative examples: a) mechanistic evaluation of differential for aging and longevity between LCR and HCR (Russ Hepple), b) test if exercise or caloric restriction in very young LCR or HCR has a long-term positive "imprinting" effect on metabolic endpoints (Charles Burant), c) interpret the large number of expression arrays being generated with a "molecular concept map" that navigates 15 databases (Arul Chinnaiyan), and 4) explore the molecular basis for higher anxiety and depression in the LCR compared to HCR (Huda Akil). The genetic and environmental variation of human populations imparts considerable difficulty to the study of complex diseases, making animal models an attractive path. The LCR and HCR are hypothesis-based models that are currently known to divide for numerous disease risks, with more likely to be defined. Information obtained from these models will immediately suggest pathways for translational studies for more effective modes of diagnosis, prevention, and treatment of complex diseases.