Intergrative Genetics of Metabolic Syndrome Traits

项目总结(见说明)： 在我们当前的PPG周期中，我们开发了一种新的方法，我们称之为“综合方法” 遗传学“，以帮助识别与代谢综合征(MetSyn)相关的基因和途径。我们还开发了一种新的小鼠图谱工具，我们将其称为”小鼠多样性面板“(MDP)，它允许高分辨率地定位特征，如基因与环境的相互作用。在本提案中，我们将把这些工具应用于关于代谢综合征的两个基本问题。 第一个问题与人类MetSyn特征背后的分子网络的性质有关。 在我们之前的“综合遗传学”研究中，我们在分离的小鼠群体中检测了分子表型(转录水平)和临床表型。这使我们能够识别控制转录水平的遗传位点，并建立共表达网络的模型。我们现在将把这种方法扩展到人类群体。与Markku Laakso博士合作，我们将检查MetSyn研究人群中1,000个人的脂肪活检中的DNA变异和转录水平，该人群已被分型为MetSyn的主要特征。然后，我们将确定与临床特征相关的基因和共表达网络。 基因与饮食的相互作用在MetSyn中至关重要，但众所周知，它们很难研究 直接在人类群体中传播。我们将使用我们的小鼠多样性小组来检查在饮食或高脂肪饮食中维持8周的小鼠在生物网络和临床特征上的差异。这将使我们能够定位MetSyn特征的饮食反应基因，并对受这些基因干扰的共表达网络进行MEDOL。 将集成鼠标和人类数据，并验证与该计划相关的方面 与其他项目和核心进行协作研究。

PROJECT SUMMARY (See Instructions): During the present cycle of our PPG, we have developed a novel approach, which we term "integrative genetics", to help identify genes and pathways associated with the Metabolic Syndrome (MetSyn). We have also developed a new mapping tool in mice, which we term a "mouse diversity panel" (MDP), which allows high resolution mapping of traits such as gene-by-environment interactions. In the present proposal, we will apply these tools to two basic questions concerning the metabolic syndrome. The first question has to do with the nature ofthe molecular networks underlying human MetSyn traits. In our previous "integrative genetics" studies, we examined both molecular phenotypes (transcript levels) and clinical phenotypes in segregating mouse populations. This allowed us to identify genetic loci controlling transcript levels and model co-expression networks. We will now extend this approach to human populations. In collaboration with Dr. Markku Laakso, we will examine DNA variation and transcript levels in fat biopsies from 1,000 individuals in a MetSyn study population that has been typed for the major MetSyn traits. We will then identify genes and co-expression networks related to clinical traits. Gene-by-diet interactions are critically important in MetSyn, but they are notoriously difficult to study directly in human populations. We will use our mouse diversity panel to examine differences in biologic networks and clinical traits in mice maintained on either a chow diet or a high fat diet for 8 weeks. This will allow us to map genes controlled dietary responsiveness of MetSyn traits and to medol to co-expression networks perturbed by these genes. The mouse and human data will be integrated and aspects relevant to this program validated in collaborative studies with other Projects and the Cores.