Resource for Rat Genetic Models of Aerobic Capacity

大鼠有氧能力遗传模型资源

• 批准号: 7795695
• 负责人: STEVEN Loyal BRITTON
• 金额: $ 48.29万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7795695
• 关键词: Accounting; Aerobic; Aerobic Exercise; Aging; Animal Model; Anxiety; Biogenesis; Bioinformatics; Breeding; Caloric Restriction; Clinical Research; Complex; Coupled; Databases; Development; Diagnosis; Diet; Diffuse; Disease; Environment; Environmental Health; Enzymes; Etiology; Evaluation; Evolution; Exercise; Exercise stress test; Family; Fatty acid glycerol esters; Future; Generations; Genetic; Genetic Models; Genotype; Goals; Health; Human; Impairment; Inbred Strain; Inbreeding; Link; Longevity; Lung; Maps; Mental Depression; Metabolic; Metabolic syndrome; Metabolism; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Motivation; Nature; Oxygen; Oxygen Consumption; Pathway interactions; Phenotype; Physiological; Population; Prevention; Rat Strains; Rattus; Research Personnel; Resources; Risk; Running; Skeletal Muscle; Source; Testing; Tissue-Specific Gene Expression; Training; Variant; Work; base; cardiovascular risk factor; disorder risk; exhaustion; fitness; imprint; interest; meter; model development; mortality; novel; programs; reconstitution; response; transcription factor; translational study

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.

描述（由申请方提供）：基于有氧能力与全因发病率和死亡率之间的强统计学相关性，假设人工选择大鼠进行低和高有氧运动能力将产生也可对比疾病风险的模型。如果这是真的，这将支持氧代谢受损是疾病风险机制基础的常见特征的观点。20代双向选择产生了低能力跑步者（LCR）和高能力跑步者（HCR）的品系，其有氧跑步机跑步能力相差超过5倍。LCR在包括代谢综合征在内的许多风险方面得分较高，HCR在最大耗氧量等健康因素方面得分较高。重要的是，LCR也对高脂肪饮食等环境健康风险做出更多反应。 长期目标是从机制上理解划分这些疾病风险对比模型的特征，并最终使这些模型成为经济上可行和自我维持的资源。具体目标是：1）继续双向人工选择，直到分歧平台，2）生成和表型LCR和HCR，用于生理和疾病风险差异的机制评估;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）通过产生一组代表运行能力5倍划分的近交系来稳定模型内的基因型。我们描述了四个正在积极进行的大规模研究作为代表性的例子：a）LCR和HCR之间老化和寿命差异的机制评估（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具有长期积极的“印记”效应（查尔斯·伯兰特），c）用导航15个数据库的“分子概念图”解释正在生成的大量表达阵列（Arul Chinnaiyan），以及4）探索LCR中与HCR（Huda阿基勒）相比更高的焦虑和抑郁的分子基础。人类群体的遗传和环境变异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道路。LCR和HCR是基于假设的模型，目前已知可以划分许多疾病风险，更有可能被定义。从这些模型中获得的信息将立即为转化研究提供途径，以更有效地诊断，预防和治疗复杂疾病。