权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

SR-B1 Sorting Signals in HDL Metabolism

SR-B1 HDL 代谢中的信号分类

基本信息

批准号：
7767725
负责人：
David Silver
金额：
$ 28.21万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-05 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7767725
关键词：
Adenoviruses Amino Acid Sequence Antiatherogenic B-Lymphocytes Bile fluid Biliary Binding C-terminal Catabolism Cell Fractionation Cell membrane Cell model Cholesterol Cholesterol Esters Confocal Microscopy Coupled Endothelial Cells Essential Amino Acids Excretory function Extrahepatic Fibrinogen Hepatic Hepatobiliary Hepatocyte High Density Lipoprotein Cholesterol High Density Lipoproteins In Vitro Integral Membrane Protein Knockout Mice Label Lipids Liver MDCK cell Measurement Measures Mediating Membrane Messenger RNA Metabolism Molecular Mus Physiologic pulse Plasma Play Process Research Personnel Role Signal Transduction Silver Site Sorting - Cell Movement Tertiary Protein Structure Testing Transmembrane Domain basolateral membrane design high density lipoprotein receptor in vivo insight mouse model mutant novel overexpression polarized cell programs research study scavenger receptor transcytosis uptake

项目摘要

Plasma high density lipoprotein (HDL) is the principal carrier of plasma cholesterol for biliary cholesterol secretion. The HDL receptor Scavenger Receptor B-l (SR-BI) mediates the uptake of HDL cholesterol and cholesteryl ester for excretion into bile, and its expression correlates with biliary cholesterol secretion. SR-BI knockout mice have a significant decrease in biliary cholesterol secretion, indicating an important role of SR-BI in that process. However, little is known regarding the molecular mechanisms by which SR-BI mediates hepatobiliary secretion of cholesterol. SR-BI is expressed on both sinusoidal and canalicular membranes in liver, and undergoes transcytosisto the canalicular membrane. The sorting signals necessary for SR-BI basolateral targeting and transcytosis to the canalicular membrane are unknown. We have defined three important factors that may regulate SR-BI subcellular sorting in liver and thus SR-BI- dependent biliary cholesterol secretion. One factor is PDZK1, a PDZ domain protein that has been shown to interact with SR-BI and to be essential to maintain hepatic SR-BI levels. A second factor is a basolateral targeting signal in the C-terminus of SR-BI, and a third factor is a cholesterol binding domain in the C- terminal transmembrane domain of SR-BI. The C-terminal transmembrane domain of SR-BI can directly bind cholesterol but is not important for SR-BI-mediated selective uptake or cholesterol efflux. Cholesterol binding by SR-BI in liver may play a role in SR-BI transcytosis. Specific Aim 1 will determine the role of PDZK1 in SR-BI sorting. We have generated a PDZK1 knockout mouse model and will use both PDZK1 deficient mice and in vitro polarized cells models to examine the role of PDZK1 in SR-BI sorting. Specific Aim 2 will delimit the basolateral targeting signal of SR-BI and test the role of this sequence in SR-BI sorting in vivo and in vitro as well as in biliary cholesterol secretion in vivo. Specific Aim 3 will test the hypothesis that the SR-BI cholesterol binding domain plays a role in SR-BI transcytosis. We will test the role of this domain in biliary cholesterol secretion in vivo and SR-BI transcytosis in vitro. These studies will provide fundamental insights into the mechanisms regulating SR-BI sorting and biliary cholesterol secretion.

高密度脂蛋白(Hdl)是胆汁中胆固醇的主要载体胆固醇分泌。高密度脂蛋白受体清道夫受体B-L(SR-BI)介导高密度脂蛋白摄取胆固醇和胆固醇酯排泄到胆汁中，其表达与胆汁胆固醇相关分泌物。SR-BI基因敲除小鼠胆汁胆固醇分泌显著减少，表明 SR-BI在这一过程中发挥了重要作用。然而，人们对其分子机制知之甚少。其中SR-BI介导肝胆胆固醇的分泌。SR-BI在正弦和正弦上均有表达肝内的小管膜，并经历跨细胞的小管膜。分选信号 SR-BI所需的基底侧靶向和对小管膜的跨细胞作用尚不清楚。我们已经定义了三个可能调节肝脏SR-BI亚细胞分选从而调节SR-BI的重要因素。依赖胆汁胆固醇分泌。其中一个因素是PDZK1，一种PDZ结构域蛋白，已被证明与SR-BI相互作用，对维持肝脏SR-BI水平至关重要。第二个因素是基底侧向靶向信号位于SR-BI的C-末端，第三个因子是C-BI中的胆固醇结合结构域。 SR-BI的末端跨膜区。SR-BI的C端跨膜结构域可直接结合胆固醇，但对SR-BI介导的选择性摄取或胆固醇流出并不重要。胆固醇结合力肝脏中的SR-BI可能在SR-BI的细胞转运中起作用。具体目标1将确定PDZK1在 SR-BI排序。我们已经建立了PDZK1基因敲除小鼠模型，并将使用这两种PDZK1缺陷小鼠体外极化细胞模型检测PDZK1在SR-BI分选中的作用。具体目标2将划定 SR-BI的基侧靶向信号及其在体内和体内SR-BI分选中的作用在体外以及体内胆汁胆固醇的分泌中也是如此。特定目标3将测试SR-BI的假设胆固醇结合区在SR-BI跨细胞作用中起着重要作用。我们将测试这个结构域在胆道中的作用体内胆固醇分泌和体外SR-BI转胞作用。这些研究将提供基本的见解探讨SR-BI分选和胆汁胆固醇分泌的调节机制。