The Collaborative Cross Project on Obesity and Diabetes

描述(申请人提供)：迄今为止，对肥胖和糖尿病等复杂疾病的基因研究还没有成功地解释遗传性对这些疾病的巨大遗传贡献。在人类身上，这些研究受到了有限的表型和环境变异的影响。在小鼠身上，交叉研究受到图谱分辨率差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，它将产生来自8个方正菌株的约300个重组近交系菌株。创始人品系加在一起占所有近交系小鼠品系全部遗传多样性的90%，人们普遍认为，近交系小鼠品系具有与人类种群一样大的遗传变异性。这些菌株将进行完全的基因分型，并将携带足够的重组，以提供高分辨率的遗传图谱。我们计划在高脂饮食中对这些菌株进行详细的表型鉴定，将生理表型(例如葡萄糖耐量、脂肪生物化学)与应用各种“组学”技术(例如转录组学、代谢组学)得出的表型结合起来。我们首次计划绘制通量测量的遗传图谱，即蛋白质、脂肪酸、胆固醇和葡萄糖的真实合成速率。本研究是关于合作十字八个亲本品系的试点项目。我们的目的是确定将要测量的表型的变异范围，以便我们可以证明对重组近交系菌株进行更大规模的研究是合理的。我们组建了一支经验丰富的团队，具有互补的专业知识：1)Alan Attie(威斯康星大学，小鼠遗传学和基因组学，脂代谢)；2)Chris Newgard(杜克大学，代谢组学)；3)Gary Churchill(杰克逊实验室；构思和开发合作十字，用于研究小鼠复杂疾病相关性状的统计方法)；4)Henri Brunengraber(凯斯西储大学，稳定同位素技术(GC-MS和核磁共振)，以测量与慢性病相关的代谢流的变化)。

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).