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Polycystic Liver Disease and ER Quality Control

多囊肝病和 ER 质量控制

基本信息

批准号：
7230126
负责人：
Erik L. Snapp
金额：
$ 24.18万
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：
2006-05-01 至 2008-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7230126
关键词：
Affect Apoptosis Benign Bile Duct Epithelium Biliary Biological Assay Calnexin Cell Line Cell Proliferation Cells Cellular biology Clip Cyst Cystic Fibrosis Disease Disruption Duct (organ) structure Endoplasmic Reticulum Etiology Failure Genes Genotype Glucosidase II Glycoproteins Hepatic Huntington Disease Immunoblotting In Vitro Investigation Label Lead Lectin Life Liquid Chromatography Mass Spectrum Analysis Membrane Membrane Glycoproteins Methods Modeling Molecular Molecular Chaperones Morphology Mutation Organism PRKCSH protein Parents Pathway interactions Phenotype Physiologic pulse Population Predisposition Process Protein-Folding Disease Proteins Pulse taking Quality Control RNA Interference Reporting Research Personnel Ribosomes Tissues base calreticulin cellular imaging cholangiocyte cofactor disease phenotype gain of function gel electrophoresis glucosidase insight knock-down mutant polycystic liver disease programs protein degradation protein folding protein function protein misfolding secretory protein stable cell line therapy development tissue culture trafficking

项目摘要

DESCRIPTION (provided by applicant): The products of the autosomal-dominant polycystic liver disease (PCLD) genes affect the folding and quality control of membrane and secretory proteins. The PCLD genes, PRKCSH and SEC63, encode the endoplasmic reticulum (ER) proteins Sec63, a cofactor for the lumenal ER chaperone BiP, and glucosidase II b, which modulates glycoprotein interactions with the lectin chaperones calnexin and calreticulin. How these mutations promote cyst formation in hepatic biliary duct cells (cholangiocytes) while remaining effectively silent in most other tissues remains unclear. To dissect the molecular mechanisms of PCLD, we will develop a tissue culture model for PCLD and will investigate the cellular consequences of the PCLD mutations. Specifically, we will 1) Establish and characterize PCLD cholangiocyte cell lines, and 2) Use the PCLD cell lines to identify downstream targets of the PCLD mutants. These studies will provide some of the first insights into the cell biology of PCLD and will identify substrates that require the activities of Sec63 and glucosidase IIb.

描述（由申请人提供）：常染色体显性多囊肝病（PCLD）基因的产物影响膜和分泌蛋白的折叠和质量控制。PCLD基因PRKCSH和SEC 63编码内质网（ER）蛋白SEC 63（内腔ER伴侣BiP的辅因子）和葡萄糖苷酶II B b（调节糖蛋白与凝集素伴侣钙连接蛋白和钙网蛋白的相互作用）。这些突变如何促进肝胆管细胞（胆管细胞）中的囊肿形成，同时在大多数其他组织中保持有效沉默，目前尚不清楚。为了剖析PCLD的分子机制，我们将建立PCLD的组织培养模型，并研究PCLD突变的细胞后果。具体而言，我们将1）建立和表征PCLD胆管细胞系，2）使用PCLD细胞系鉴定PCLD突变体的下游靶标。这些研究将为PCLD的细胞生物学提供一些初步见解，并将确定需要Sec63和葡萄糖苷酶IIb活性的底物。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Evolutionary gain of function for the ER membrane protein Sec62 from yeast to humans.

DOI：
10.1091/mbc.e09-08-0730
发表时间：
2010-03-01
期刊：
Molecular biology of the cell
影响因子：
3.3
作者：
Müller L;de Escauriaza MD;Lajoie P;Theis M;Jung M;Müller A;Burgard C;Greiner M;Snapp EL;Dudek J;Zimmermann R
通讯作者：
Zimmermann R

Design and use of fluorescent fusion proteins in cell biology.