Molecular mechanisms of basolateral targeting in polarized epithelial cells

极化上皮细胞基底外侧靶向的分子机制

基本信息

批准号：
8133705
负责人：
HEIKE FOLSCH
金额：
$ 30.71万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8133705
关键词：
1-Phosphatidylinositol 3-Kinase Apical Applications Grants Architecture Biochemical Biological Cell Line Cell Polarity Cell membrane Cell physiology Cells Clathrin Clathrin Adaptors Coated vesicle Complex Connective Tissue Data Endocytosis Endosomes Ensure Environment Epithelial Epithelial Cells Excretory function Exocytosis Face Family Genetic Goals Grant Hormones Human body In Vitro Inositol Integral Membrane Protein Lead Link Lipids Maintenance Mediating Membrane Membrane Protein Traffic Methods Molecular Monomeric GTP-Binding Proteins Mutate Nutrient Organ Pathway interactions Phosphotransferases Play Positioning Attribute Post-Translational Protein Processing Process Production Proteins Recruitment Activity Recycling Regulation Research Role Sorting - Cell Movement Surface Testing Tight Junctions Vesicle Waste Products Work apical membrane base basolateral membrane follow-up lipid metabolism phosphatidylinositol 3,4,5-triphosphate phosphatidylinositol 4-phosphate phosphoinositide-3,4,5-triphosphate public health relevance receptor trans-Golgi Network uptake vesicular stomatitis virus G protein

项目摘要

DESCRIPTION (provided by applicant): Polarized epithelial cells line every organ and are of utmost importance for the function of the human body. Central to epithelial cell function is the establishment and maintenance of biochemically and functionally distinct membrane domains, the apical membrane facing the lumen of an organ and the basolateral membrane that is in contact with connective tissues. Both membranes are separated by tight junctions. To maintain this architecture, epithelial cells must continuously sort newly synthesized and internalized transmembrane receptors to the correct membrane domains in the biosynthetic and endocytic pathways. Our work focuses on the molecular mechanisms that ensure correct targeting to the basolateral membrane from a central sorting station, the recycling endosomes. Previously we showed that cargos destined for the basolateral membrane are recognized by the epithelial-specific clathrin adaptor complex AP-1B for incorporation into AP-1B vesicles. This grant application proposes to follow up on these findings and to investigate the molecular mechanisms of AP-1B function, membrane recruitment, and regulation of the AP-1B-dependent pathway from recycling endosomes to the basolateral membrane. We will employ genetical, biochemical, and cell biological methods to accomplish our research goals. PUBLIC HEALTH RELEVANCE: The primary function of epithelial cells is to ensure the correct nutrient and waste product exchange between the body and the environment. To fulfill these different functions, the surface of epithelial cells is divided into biochemically and functionally distinct membrane domains. Our long-term goal is to understand how polarized epithelial cells establish and maintain this asymmetry with a focus on processes that lead to correct targeting of transmembrane receptors to the membrane domain that faces connective tissues and neighboring cells.

描述（由申请人提供）：极化上皮细胞围绕着每个器官，对人体的功能至关重要。上皮细胞功能的核心是生化和功能上不同的膜结构域的建立和维护，面向器官腔的顶部膜和与结缔组织接触的基底外侧膜。这两个膜都被紧密的连接处隔开。为了维持这种体系结构，上皮细胞必须在生物合成和内吞途径中连续分类新合成和内部化的跨膜受体。我们的工作着重于确保从中央分类站（回收内体）正确靶向基底外侧膜的分子机制。以前，我们表明，上皮特异性网旋蛋白适配器复合物AP-1B识别为基底外侧膜的赤道识别，以掺入AP-1B囊泡中。该赠款的应用建议跟进这些发现，并研究AP-1B功能，膜募集的分子机制，以及从回收内体到基底外侧膜的AP-1B依赖途径的调节。我们将采用遗传，生化和细胞生物学方法来实现我们的研究目标。公共卫生相关性：上皮细胞的主要功能是确保身体与环境之间正确的营养和废物产品交换。为了实现这些不同的功能，将上皮细胞的表面分为生化和功能上不同的膜结构域。我们的长期目标是了解两极分化的上皮细胞如何建立和维持这种不对称性，重点是导致将跨膜受体纠正靶向面向结缔组织和邻近细胞的膜结构域的过程。