The Collaborative Cross Project on Obesity and Diabetes

描述（由申请人提供）：肥胖和糖尿病等复杂疾病的遗传研究迄今尚未成功解释遗传性对这些疾病的巨大遗传贡献。在人类中，这些研究受到有限的表型和环境变化的影响。在小鼠中，互交研究受到较差的定位分辨率和缺乏生物复制的限制。协作杂交是一个正在开发的大型社区资源，将产生约300个来自8个创始菌株的重组近交系。建立者品系共同占所有近交系小鼠品系的所有遗传多样性的约90%，人们普遍认为，近交系小鼠具有与人类种群一样多的遗传变异性。这些菌株将被完全基因分型，并将携带足够的重组，以提供高分辨率的遗传图谱。我们计划对这些菌株进行详细的高脂饮食表型分析，将生理表型分析（例如葡萄糖耐量，脂质生物化学）与应用各种“组学”技术（例如转录组学，代谢组学）获得的表型结合在一起。这是第一次，我们计划从遗传学上绘制通量测量;即蛋白质、脂肪酸、胆固醇和葡萄糖的真实合成速率。本研究是对8个亲本株系进行的合作杂交试验。我们的目的是确定将测量的表型的变异范围，以便我们可以证明重组近交系的更大研究是合理的。我们组建了一支经验丰富的团队，拥有互补的专业知识; 1）Alan Attie（威斯康星州大学;小鼠遗传学和基因组学，脂质代谢）; 2）Chris Newgard（杜克大学;代谢组学）; 3）加里丘吉尔（杰克逊实验室;构想并开发了协作杂交，用于调查小鼠复杂疾病相关性状的统计方法）;和4）Henri Brunengraber（凯斯西储大学;稳定同位素技术（GC-MS和NMR），用于测量与慢性疾病相关的代谢通量的变化）。

DESCRIPTION (provided by applicant): Genetic studies of complex diseases like obesity and diabetes have so far not succeeded in explaining the large genetic contribution of heritability to these disorders. In humans, the studies are compromised by limited phenotyping and environmental variation. In mice, intercross studies are limited by poor mapping resolution and the lack of biological replication. The Collaborative Cross is a large community resource under development that will generate ~300 recombinant inbred strains derived from eight founder strains. The founder strains together account for ~90% of all the genetic diversity of all the inbred mouse strains, which it is widely believed, carry about as much genetic variability as the human population. The strains will be fully genotyped and will carry enough recombinations to afford high-resolution genetic mapping. We plan to carry out detailed phenotyping of these strains on high-fat diets, bringing together physiological phenotyping (e.g. glucose tolerance, lipid biochemistry) with phenotypes derived from the application of various "-omics" technologies (e.g. transcriptomics, metabolomics). For the first time, we plan to genetically map flux measurements; i.e. the true rates of synthesis of proteins, fatty acids, cholesterol, and glucose. This study is a pilot project on the eight parental strains ofthe Collaborative Cross. Our aim is to ascertain the range of variability of the phenotypes will measure so that we can justify a larger study of the recombinant inbred strains. We have assembled an experienced team with complementary expertise; 1) Alan Attie (University of Wisconsin; mouse genetics & genomics, lipid metabolism); 2) Chris Newgard (Duke University; metabolomics); 3) Gary Churchill (The Jackson Laboratory; conceived and developed the Collaborative Cross, statistical methods for the investigation of complex disease-related traits in the mouse); and 4) Henri Brunengraber (Case Western Reserve University; stable isotope technology (GC-MS and NMR) to measure changes in metabolic flux associated with chronic diseases).