Genetic Factors in Lipid Metabolism: Mouse Model.

该项目是我们二十年前PPG原始周期中一个项目的延续。这个概念是应用小鼠遗传学的力量来了解体内复杂的生理，细胞和分子相互作用，导致心血管疾病和代谢综合征。在目前的资助中，我们在小鼠中定位克隆了一个基因，该基因导致了联合高脂血症表型。该基因被证明对应于硫氧还蛋白相互作用蛋白（Txnip），这是一种了解甚少的蛋白质，可结合硫氧还蛋白并使其失活。我们最近的研究和其他实验室的研究表明Txnip参与了脂质和葡萄糖代谢的基本调节。我们现在将使用我们的小鼠模型来研究所涉及的机制。 我们在小鼠遗传研究中发现的另一种蛋白质是载脂蛋白AII（apoAII）。我们已经表明，这种蛋白质的水平，范围从零（apoAII敲除）到几mg/dl（SM株）到大约20 mg/dl（C57 BL/6株）到大约30 mg/dl（BALB/c株）到大约100 mg/dl（apoAII转基因），对胰岛素抵抗、甘油三酯水平、体脂、动脉粥样硬化和HDL的炎症性质具有连续的显著影响。我们现在建议进一步研究所涉及的因果相互作用。第三个目标是在小鼠中定位克隆一个新的基因，该基因与混合型高脂血症和动脉粥样硬化有关。 最后一个目的是在小鼠中研究一个基因，该基因在芬兰家族性合并高脂血症家系研究中的当前资助中被定位克隆。基因，USF 1，将在敲除和转基因小鼠模型的各种背景下进行检查。项目I将与其他项目以及所有核心进行交互。

This project is a continuation of a project in the original cycle of our PPG two decades ago. The concept is to apply the power of mouse genetics to understand, in vivo, the complex physiologic, cellular and molecular interactions that contribute to cardiovascular disease and the metabolic syndrome. During the current grant, we positionally cloned a gene in mouse that results in a combined hyperlipidemic phenotype. The gene proved to correspond to thioredoxin interacting protein (Txnip), a poorly understood protein that binds to and inactivates thioredoxin. Our recent studies and those of other laboratories have now implicated Txnip in fundamental regulation of both lipid and glucose metabolism. We will now examine the mechanisms involved using our mouse model. Another protein that we identified in genetic studies in mice is apolipoprotein All (apoAII). We have shown that the levels of this protein, ranging from null (apoAII knockout) to a few mg/dl (strain SM) to approximately 20 mg/dl (strain C57BL/6) to approximately 30 mg/dl (strain BALB/c) to approximately 100 mg/dl (apoAII transgenic) have ;a continuous, significant impact on insulin resistance, triglyceride levels, body fat, atherosclerosis and inflammatory properties of HDL. We now propose to further pursue the causal interactions involved. The third aim is to positionally clone a novel gene in mouse that contributes to combined hyperlipidemia and atherosclerosis. The last aim is to study in mouse a gene that was positionally cloned in the current grant in studies of Finnish familial combined hyperlipidemic pedigrees. The gene, USF1, will be examined in knockout and transgenic mouse models on a variety of backgrounds. Project I will interact with each of the other projects and with all the cores.