Polycystic Liver Disease and ER Quality Control

多囊肝病和 ER 质量控制

• 批准号: 7082626
• 负责人: Erik L. Snapp
• 金额: $ 20.72万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 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/7082626
• 关键词: RNA interference; apoptosis; autosomal dominant trait; bile ducts; cell line; cell proliferation; cellular pathology; endoplasmic reticulum; enzyme activity; enzyme structure; enzyme substrate; gene mutation; glycoproteins; hydrolase; liver; liver disorder; membrane proteins; model; model design /development; molecular pathology; pathologic process; protein structure function; tissue /cell culture

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 SEC63 编码内质网 (ER) 蛋白 Sec63（腔内 ER 伴侣 BiP 的辅助因子）和葡萄糖苷酶 II b（调节糖蛋白与凝集素伴侣钙联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）中囊肿的形成，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，我们将开发 PCLD 的组织培养模型，并研究 PCLD 突变的细胞后果。具体来说，我们将 1) 建立和表征 PCLD 胆管细胞系，2) 使用 PCLD 细胞系来识别 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。