Role of PDZK1 in lipid metabolism and atherosclerosis.

PDZK1 在脂质代谢和动脉粥样硬化中的作用。

• 批准号: 7480259
• 负责人: Olivier N. Kocher
• 金额: $ 41.27万
• 依托单位: BETH ISRAEL DEACONESS 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 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7480259
• 关键词: Adaptor Signaling Protein; Adhesions; Adrenal Cortex; Amino Acid Sequence; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Binding; Biological; Biological Process; Carcinoma; Cardiomyopathies; Cardiovascular Diseases; Carrier Proteins; Cell Surface Receptors; Cell membrane; Cells; Chloride Anion Exchanger; Chloride Channels; Cholesterol; Complex; Cystic Fibrosis Transmembrane Conductance Regulator; Cytoplasm; Development; Diet; Dominant-Negative Mutation; Drug resistance; Family; Genes; Goals; Hepatic; Hepatocyte; High Density Lipoproteins; Human; Hyperlipidemia; Intervention; Ion Channel; Ions; Knock-out; Knockout Mice; Laboratories; Left; Link; Lipoproteins; Liver; Location; Low Density Lipoprotein Receptor; Mediating; Membrane; Membrane Protein Traffic; Membrane Proteins; Metabolism; Modality; Multi-Drug Resistance; Multidrug Resistance-Associated Proteins; Mus; Names; Nature; Numbers; Organ; Ovary; PDZ protein; Pharmacologic Substance; Phosphotyrosine; Plasma; Play; Proteins; Research Personnel; Role; Role playing therapy; SR-BI receptor; Scaffolding Protein; Signal Transduction; Signaling Protein; Small Intestines; Tertiary Protein Structure; Testing; Testis; Tissues; Transgenes; Transgenic Mice; cancer cell; chemotherapeutic agent; high density lipoprotein receptor; hypercholesterolemia; interest; lipid metabolism; multidrug resistance-associated protein 2; novel; numb protein; programs; protein expression; receptor; reverse cholesterol transport; scaffold; scavenger receptor; sodium-phosphate cotransporter proteins; therapeutic target

DESCRIPTION (provided by applicant): Adaptor, anchoring and scaffolding proteins play an important role in signal transduction. In many situations, the interaction between signaling proteins is mediated by small amino acid sequences binding to specific proteins domains, such as src homology (SH), pTyr-binding (PTB) or PDZ domains. These interactions are responsible for determining location, function and activity of receptors and transporter proteins among others. A few years ago, we isolated a novel protein that we named PDZK1. PDZK1, contains four PDZ protein-interactions domains and interacts with the carboxy-terminal portion of a number of membrane associated proteins including cMOAT (MRP2) the canalicular multispecific organic anion transporter associated with multidrug resistance, the cystic fibrosis transmembrane conductance regulator CFTR, the chloride channel CLC-3B, the type lla Na/Pi cotransporter, the Na-H exchanger NHE3, the chloride-anion exchanger CFEX and the high density lipoprotein (HDL) scavenger receptor SR-BI. These new findings define PDZK1 as a major player in the organization of membrane associated proteins including cell surface receptors and ion transporters. As a result, PDZK1 is likely to play an important role in biological processes as diverse as lipid metabolism and cardiovascular disease, ion channel organization and multidrug resistance. We generated a PDZK1 knockout mouse which is characterized by increased plasma cholesterol levels and markedly reduced expression of SR-BI in the liver, resulting in impaired "reverse cholesterol transport." PDZK1 joins ARM (the product of the defective gene in autosomal recessive hypercholesterolemia) in what is likely to be a growing family of cytoplasmic adaptor proteins that control the tissue specific activity of cell surface receptors. The goals of this proposal are: 1) to determine if a functional PDZK1 gene is protective against the development of atherosclerosis, 2) to study the nature of the interaction between PDZK1 and SR-BI in the liver and understand the role played by PDZK1 in optimizing reverse cholesterol transport, 3) to identify the putative molecule that plays the role of PDZK1 in the organization of SR-BI in steroidogenic organs.

描述（由申请人提供）：适配器，锚定和脚手架蛋白在信号转导中起重要作用。在许多情况下，信号蛋白之间的相互作用是由与特定蛋白质结构域结合的小氨基酸序列介导的，例如SRC同源性（SH），PTYR结合（PTB）或PDZ结构域。这些相互作用负责确定受体和转运蛋白的位置，功能和活性。几年前，我们隔离了一种新的蛋白质，该蛋白质命名为PDZK1。 PDZK1, contains four PDZ protein-interactions domains and interacts with the carboxy-terminal portion of a number of membrane associated proteins including cMOAT (MRP2) the canalicular multispecific organic anion transporter associated with multidrug resistance, the cystic fibrosis transmembrane conductance regulator CFTR, the chloride channel CLC-3B, the type lla Na/pi共转运蛋白，Na-H交换器NHE3，氯化物交换器CFEX和高密度脂蛋白（HDL）清除剂受体SR-BI。这些新发现将PDZK1定义为包括细胞表面受体和离子转运蛋白的膜相关蛋白质组织的主要参与者。结果，PDZK1可能在脂质代谢和心血管疾病，离子通道组织和多药耐药等多种多样的生物过程中起重要作用。 我们产生了一种PDZK1敲除小鼠，其特征是血浆胆固醇水平升高，并显着降低了肝脏中SR-BI的表达，从而导致“反向胆固醇转运”受损。 PDZK1与ARM（常染色体隐性高胆固醇血症中缺陷基因的产物）在可能不断增长的细胞质衔接蛋白家族中，从而控制细胞表面受体的组织特异性活性。 该提案的目标是：1）确定功能性PDZK1基因是否可以防止动脉粥样硬化的发展，2）研究肝脏中PDZK1和SR-BI之间相互作用的性质器官。