Genetic Factors in Lipid Metabolism: Mouse Model.

这个项目是二十年前我们PPG最初周期中的一个项目的延续。其概念是应用小鼠遗传学的力量，在体内了解导致心血管疾病和代谢综合征的复杂生理、细胞和分子相互作用。在目前的资助期间，我们在小鼠身上定位克隆了一个导致混合型高脂血症的基因。该基因被证明与硫氧还蛋白相互作用蛋白(TXNIP)相对应，TXNIP是一种鲜为人知的蛋白质，与硫氧还蛋白结合并使其失活。我们最近的研究和其他实验室的研究表明，TXNIP参与了脂肪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检查所涉及的机制。 我们在小鼠的遗传学研究中发现的另一种蛋白质是载脂蛋白ALL(ApoAII)。我们已经证明，这种蛋白质的水平，从零(apoAII基因敲除)到几mg/dl(菌株SM)，到大约20 mg/dl(菌株C57BL/6)，大约30 mg/dl(菌株BALB/c)到大约100 mg/dl(apoAII转基因)；对胰岛素抵抗、甘油三酯水平、体脂、动脉粥样硬化和高密度脂蛋白的炎症特性有持续而显著的影响。我们现在建议进一步探讨所涉及的因果相互作用。第三个目标是在小鼠身上定位克隆一个导致高脂血症和动脉粥样硬化的新基因。 最后一个目标是在小鼠身上研究芬兰家族性混合型高脂血症家系研究中定位克隆的基因。这种名为USF1的基因将在各种背景下的基因敲除和转基因小鼠模型中进行检测。项目I将与其他每个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.