Characterization of the role of ARH on LDLR function

ARH 对 LDLR 功能作用的表征

• 批准号: 8238866
• 负责人: Peter A. Michaely
• 金额: $ 23.79万
• 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/8238866
• 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. PUBLIC HEALTH RELEVANCE: Our published data show that the LDL receptor (LDLR) handles LDL and VLDL differently during uptake. This proposal will characterize how the LDLR distinguishes LDL from VLDL and determine how S-nitrosylation of the ARH adaptor protein regulates the LDL uptake process.

描述(申请人提供)：低密度脂蛋白受体(LDLR)是主要的内吞受体，可将低密度脂蛋白及其脂蛋白前体极低密度脂蛋白残留物从循环中移除。低密度脂蛋白受体功能缺陷会提高低密度脂蛋白-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病。长期以来，低密度脂蛋白受体一直被视为一种简单的内吞受体，当受体经历结构性内吞作用时，它会携带结合的脂蛋白。前一个供资期间支持的研究表明，LDLR更复杂，因为LDLR区分脂蛋白摄取过程中的低密度脂蛋白和极低密度脂蛋白残留物。这项提议的初步数据显示，低密度脂蛋白和极低密度脂蛋白通过内体进行不同的运输，这种运输差异使低密度脂蛋白比极低密度脂蛋白残留物降解得更快。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。与这种可能性一致，我们的初步数据显示，低密度脂蛋白受体摄取低密度脂蛋白需要ARH接头蛋白的S亚硝化，而不是极低密度脂蛋白的残留摄取。这项建议的两个目标是(I)确定LDLR如何区分脂蛋白摄取过程中的低密度脂蛋白和极低密度脂蛋白残留物和(Ii)确定ARH亚硝酸化如何调节低密度脂蛋白摄取。为了实现第一个目标，拟议的研究将检验这样一个假设，即多个LDLR结合单个VLDL残留物的能力会影响LDLR如何内化VLDL残留物。这些研究还将描述低密度脂蛋白和极低密度脂蛋白在内体中的不同处理方式。为了实现第二个目标，拟议的研究将检验这样一个假设，即ARH亚硝化是将LDLR-LDL复合体靶向涂层凹坑所必需的。第二个目标下的研究还将检验一氧化氮对ARH功能的调节控制体内低密度脂蛋白摄取的假设。 公共卫生相关性：我们公布的数据显示，低密度脂蛋白受体(LDLR)在摄取过程中处理低密度脂蛋白和极低密度脂蛋白的方式不同。这项建议将描述低密度脂蛋白受体如何区分低密度脂蛋白和极低密度脂蛋白，并确定ARH接头蛋白的S亚硝化如何调节低密度脂蛋白的摄取过程。