A Mouse Model for Complex Human Diseases

描述(改编自申请人的摘要)：我们建议完成 白粉病杂交形成的一大系列抗性菌株的选育 LG/J和SM/J小鼠品系。这些菌株已经完成了三分之二的 达到有效近亲繁殖状态所需世代的数量。我们还将 在这些菌株中获得大量的多态微卫星标记 将它们从基因上定性为我们自己的工作和其他人的工作 RI菌株集。除了开发RI菌株外，我们还将保持 AI品系。该菌株是从同一个F2代随机交配而成的 用于产生RI菌株的群体。RI和Al的结合 来自同一杂交组合的菌株将是一个强大的量化资源 一系列性状的性状基因座定位。我们将测试RI 母体遗传变异对新生儿和成人影响的菌株 利用40个RI品系与标准品系的正反交进行表型分析 近交系，C57BL/6J。在这个设计中，基因不同的母亲给了 产生基因相同的后代，从而产生互惠的差异 对母亲养育后代的环境的遗传影响。在……里面 此外，我们还将检验“节俭表现型”假说，即 出生前和新生儿的环境影响疾病的风险(高血压、 糖尿病、肥胖症、冠心病等)在成年后。差劲 营养不良的新生儿在宫内及以后不久就能适应低营养水平 出生。这种适应一直持续到成年，所以他们特别 在晚年容易受到高脂肪饮食的有害影响。这个 来自正反交的后代将获得高脂肪或低脂肪 断奶后的饮食。我们将测试动物是否受到相对较差的 出生前和新生儿的环境对高脂肪饮食的反应更强烈。我们 将定位这些遗传母体效应的数量性状基因座及其 与饮食的互动。

DESCRIPTION (Adapted from the applicant's abstract): We propose to complete the development of a large series of 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 addition to developing RI strains, we will maintain an AI strain. This strain was formed by random mating from the same F2 population used in generating the RI strains. The combination of RI and Al 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 low nutrition 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.