Use Of Animal Models To Study Genes That Modulate Atherosclerosis

使用动物模型研究调节动脉粥样硬化的基因

• 批准号: 10008759
• 负责人: Alan Thomas Remaley
• 金额: $ 103.09万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10008759
• 关键词: Affect; Animal Model; Apolipoproteins C; Atherosclerosis; Biological Assay; Biological Markers; Cell membrane; Cells; Cholesterol; Chylomicrons; Clinical; Coronary heart disease; Dietary Intervention; Future; Genes; Golgi Apparatus; High Density Lipoproteins; Human; Intestines; Knockout Mice; Legal patent; Libraries; Lipoproteins; Metabolism; Mouse Strains; Paper; Phage Display; Proteins; Publishing; Sampling; System; Testing; Tissues; Triglyceride Metabolism; cardiovascular risk factor; in vivo; lipid metabolism; mouse model; novel; novel therapeutics; off-patent; rab GTP-Binding Proteins; trafficking; Affect; Animal Model; Apolipoproteins C; Atherosclerosis; Biological Assay; Biological Markers; Cell membrane; Cells; Cholesterol; Chylomicrons; Clinical; Coronary heart disease; Dietary Intervention; Future; Genes; Golgi Apparatus; High Density Lipoproteins; Human; Intestines; Knockout Mice; Legal patent; Libraries; Lipoproteins; Metabolism; Mouse Strains; Paper; Phage Display; Proteins; Publishing; Sampling; System; Testing; Tissues; Triglyceride Metabolism; cardiovascular risk factor; in vivo; lipid metabolism; mouse model; novel; novel therapeutics; off-patent; rab GTP-Binding Proteins; trafficking

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.

在过去的一年中，我们继续使用商业上可用的和独特的小鼠菌株来研究脂蛋白代谢和动脉粥样硬化之间的关联。 我们的许多涉及动物模型的论文都列在其他项目下。 在过去一年中，我们在该项目下列出的主要成就之一是发现了一个名为Dennd5b的新基因，我们发现它参与了肠道乳糜微粒分泌。 通过噬菌体显示库鉴定了靶基因，并使完整的KO小鼠确认该基因在脂质代谢中的重要性。 DENNDD5B编码像Rab-GTPase这样的蛋白质，该蛋白似乎参与了从高尔基体运输到质膜到质膜的乳糜微粒，该蛋白是使用我们制造的KO小鼠菌株发现的。 过去一年中的另一个主要成就是使用与HDL相关的各种动物模型，这些模型用于开发无细胞的测定系统，以检查HDL对外排过多的细胞胆固醇的能力。 该测定法已申请了一项专利，我们计划将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。在过去的一年中，我们也成功制作了，但尚未发表有条件的APOC-III KO小鼠，以选择性地删除各种组织中的APOC-III基因，以检查其对甘油三酸酯代谢的影响。