Use Of Animal Models To Study Genes That Modulate Atherosclerosis

在过去的一年里，我们继续使用我们开发的商业上可用的和独特的小鼠品系来研究脂蛋白代谢和动脉粥样硬化之间的关联。 我们发表的许多涉及动物模型的论文都列在我们的其他项目下。 我们在过去一年中的主要成就之一是发现了一种名为DENND 5 B的新基因，我们发现该基因与肠道乳糜微粒分泌有关。 通过噬菌体展示文库鉴定了目的基因，并制备了完整的KO小鼠，证实了该基因在脂质代谢中的重要性。DENNDD 5 B编码一种RAB-GT3样蛋白，该蛋白似乎参与乳糜微粒从高尔基体到质膜的运输，这是使用我们制备的KO小鼠品系发现的。 过去一年的另一个主要成就是使用我们与HDL相关的各种动物模型，用于开发无细胞测定系统，以检查HDL排出过量细胞胆固醇的能力。 该检测方法已申请专利，我们计划在未来探索其作为人类样本中心血管风险生物标志物的临床实用性。我们也在过去一年中成功制作了但尚未发表的条件性apoC-III KO小鼠，选择性地删除apoC-III基因在各种组织中的表达，以检测其对甘油三酯代谢的影响。

In the past year, we have continued to use both commercially available and unique mouse strains that we have developed to investigate the association between lipoprotein metabolism and atherosclerosis. Many of our published papers involving animal models are listed under our other projects. One of our main accomplishments in the past year that is listed under this project is the discovery of a novel gene called DENND5B that we have found to be involved in intestinal chylomicron secretion. The target gene was identified by a phage display library and a complete KO mouse was made confirming the importance of this gene in lipid metabolism. DENNDD5B encodes for a RAB-GTPase like protein that appears to be involved in trafficking of chylomicrons from the Golgi to the plasma membrane, which was uncovered using the KO mouse strain that we made. The other main accomplishment in the past year was the use of our various animal models related to HDL that were used to develop a cell-free assay system to examine the ability of HDL to efflux excess cellular cholesterol. A patent was filed on the assay and we plan to explore in the future its clinical utility as a cardiovascular risk biomarker in human samples. We have also successfully made in the past year but have not published yet a conditional apoC-III KO mice to selectively delete the apoC-III gene in various tissues to examine its effect on triglyceride metabolism.