Characterization of the role of ARH on LDLR function

ARH 对 LDLR 功能作用的表征

• 批准号: 8583338
• 负责人: Peter A. Michaely
• 金额: $ 23.37万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8583338
• 关键词: Adaptor Signaling Protein; Address; Atherosclerosis; Behavior; Binding; Blood Circulation; Calcium; Calcium-Sensing Receptors; Cholesterol; Clathrin; Complex; Coronary Arteriosclerosis; Cysteine; Cytoplasmic Tail; Data; Defect; Endocytosis; Endosomes; Extracellular Domain; Familial Hypercholesterolemia; Fatty acid glycerol esters; Fluorescence Microscopy; Funding; Goals; In Vitro; Individual; LDL Cholesterol Lipoproteins; Lipoprotein Binding; Lipoproteins; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Mediating; Mutation; Nitric Oxide; Nitric Oxide Synthase; Play; Post-Translational Protein Processing; Process; Publishing; Recycling; Regulation; Role; Testing; Very low density lipoprotein; coated pit; early onset; experience; hypercholesterolemia; in vivo; insight; receptor; receptor function; response; trafficking; uptake

DESCRIPTION (provided by applicant): The LDL receptor (LDLR) is the principal endocytic receptor that removes both LDL and its lipoprotein precursor, VLDL remnants, from the circulation. Defects in LDLR function elevate LDL-cholesterol levels (hypercholesterolemia), promoting atherosclerosis and early onset of coronary artery disease. The LDLR has long been viewed as a simple endocytic receptor, carrying in bound lipoprotein when the receptor undergoes constitutive endocytosis. Studies supported by the prior funded period show that the LDLR is more sophisticated in that the LDLR distinguishes between LDL and VLDL remnants during lipoprotein uptake. Preliminary data for this proposal shows that LDL and VLDL traffic differently through endosomes and that this trafficking difference allows LDL to be degraded faster than VLDL remnants. Use of different endocytic mechanisms for each lipoprotein provides the opportunity to regulate each process independently. Consistent with this possibility, our preliminary data show that S-nitrosylation of the ARH adaptor protein is required for LDL uptake, but not VLDL remnant uptake, by the LDLR. The two goals of this proposal are (i) to determine how the LDLR distinguishes between LDL and VLDL remnants during lipoprotein uptake and (ii) to determine how ARH nitrosolation regulates LDL uptake. To achieve the first goal, proposed studies will test the hypothesis that the ability of multiple LDLRs to bind individual VLDL remnants informs how the LDLR internalizes VLDL remnants. These studies will also characterize how LDL and VLDL are differentially processed in endosomes. To achieve the second goal, the proposed studies will test the hypothesis that ARH nitrosylation is necessary for targeting LDLR-LDL complexes to coated pits. Studies under the second goal will also test the hypothesis that nitric oxide regulation of ARH function controls LDL uptake in vivo.

性状（由申请人提供）：LDL受体（LDLR）是从循环中清除LDL及其脂蛋白前体VLDL残留物的主要内吞受体。LDLR功能缺陷会升高LDL-胆固醇水平（高胆固醇血症），促进动脉粥样硬化和冠状动脉疾病的早期发作。LDLR长期以来被认为是一种简单的内吞受体，当受体经历组成性内吞作用时携带结合的脂蛋白。前期资助的研究表明，LDLR更复杂，因为LDLR在脂蛋白摄取期间区分LDL和VLDL残留。该提案的初步数据表明，LDL和VLDL通过内体的运输方式不同，这种运输差异使LDL比VLDL残留物降解得更快。对每种脂蛋白使用不同的内吞机制提供了独立调节每个过程的机会。与这种可能性相一致，我们的初步数据表明，S-亚硝基化的ARH衔接蛋白所需的LDL摄取，但不是极低密度脂蛋白残留的摄取，由LDLR。该提案的两个目标是（i）确定LDLR如何在脂蛋白摄取过程中区分LDL和VLDL残留物，以及（ii）确定ARH亚硝化如何调节LDL摄取。为了实现第一个目标，拟定的研究将检验以下假设：多个LDLR结合单个VLDL残余物的能力告知LDLR如何内化VLDL残余物。这些研究还将表征LDL和VLDL如何在内体中差异加工。为了实现第二个目标，拟议的研究将测试ARH亚硝基化是将LDLR-LDL复合物靶向包被凹坑所必需的假设。第二个目标下的研究也将检验一氧化氮调节ARH功能控制体内LDL摄取的假设。