A Mouse Model for Complex Human Diseases

超出提供的空间。我们建议完成由LG/J和SM/J小鼠品系杂交形成的一大系列重组近交系(RI)的开发。这些品系已经完成了达到有效近亲繁殖状态所需世代的三分之二。我们还将对这些菌株中的大量多态微卫星标记进行评分，以便为我们自己的工作和使用RI菌株集的其他人的工作确定它们的遗传学特征。除了发展RI品系外，我们还将保持一个高级杂交(AI)品系。该菌株是从用于产生RI菌株的同一F2群体中随机交配而成的。来自同一杂交组合的RI和AI品系的组合将成为对各种性状进行数量性状基因座定位的强大资源。我们将利用RI品系与标准近交系C57BL/6J之间的40个正反交，测试RI品系在母体对新生儿和成年表型的影响方面的遗传变异。在这个设计中，基因不同的母亲产生的后代基因相同，因此，相互的差异是由于母亲为子女提供的环境的遗传影响。此外，我们还将测试“节俭表现型”假说，该假说认为出生前和新生儿的环境会影响疾病(高血压、糖尿病、肥胖症、冠心病等)的风险。在成年后。营养不良的新生儿适应子宫内和出生后不久的低营养水平。这种适应一直持续到成年，所以他们在以后的生活中特别容易受到高脂肪饮食的有害影响。反交后代将在断奶后接受高脂肪或低脂肪饮食。我们将测试在相对较差的前期和新生儿环境下的动物是否对高脂肪饮食有更强烈的反应。我们将绘制这些遗传母体效应及其与饮食相互作用的数量性状基因座图。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. We propose to completethe developmentof a large series of recombinant inbred (RI) strains formed from the intercross of LG/J and SM/J mouse strains. These strains have already completed two-thirds of the generations needed to reach effective inbred status. We will also score a large number of polymorphic microsatellite markers in these strains to genetically characterize them for our own work and the work of others using the RI strain set. In additionto developing RI strains, we will maintain an advanced intercross (AI)strain. This strain was formed by random mating from the same F2 populationused in generating the RI strains. The combination of RI and AI strains from the same intercross will be a powerful resource for quantitative trait locus mapping for a wide variety of characters. We will test the RI strains for genetic variation in maternal effects on both neonatal and adult phenotypes using 40 reciprocal crosses between the RI strains and a standard inbred strain, C57BL/6J. In this design genetically different mothers give rise to genetically identical offspring so that reciprocal differences are due to genetic effects on the environment a mother provides for her offspring. In addition, we will test the "thrifty phenotype" hypothesis that states that pre- and neonatal environment affects risk for diseases (hypertension, diabetes, obesity, coronary artery disease, etc.) in adulthood. Poorly nourished neonates adapt to lownutrition levels in utero and soon after birth. This adaptation persists into adulthood so they are particularly susceptible to the deleterious effects of a high fat diet later in life. The offspring from the reciprocal crosses will receive either a high or a low fat diet after weaning. We will test whether animals subjected to relatively poor pre-and neonatal environments respond more strongly to the high fat diet. We will map quantitative trait loci for these genetic maternal effects and their interaction with diet. PERFORMANCE SITE ========================================Section End===========================================