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）：极化上皮细胞排列在每个器官中，对于人体的功能至关重要。上皮细胞功能的核心是建立和维持生物化学和功能上不同的膜域，即面向器官内腔的顶膜和与结缔组织接触的基底外侧膜。两层膜由紧密连接分开。为了维持这种结构，上皮细胞必须不断地将新合成和内化的跨膜受体分类到生物合成和内吞途径中的正确膜域。我们的工作重点是确保从中央分选站（回收内体）正确靶向基底外侧膜的分子机制。之前我们表明，运往基底外侧膜的货物被上皮特异性网格蛋白接头复合物 AP-1B 识别，并掺入 AP-1B 囊泡中。本拨款申请旨在跟进这些发现，并研究 AP-1B 功能、膜募集以及从内体循环到基底外侧膜的 AP-1B 依赖性途径的调节的分子机制。我们将采用遗传学、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交换。为了实现这些不同的功能，上皮细胞的表面被分为生化和功能上不同的膜域。我们的长期目标是了解极化上皮细胞如何建立和维持这种不对称性，重点关注导致跨膜受体正确靶向面向结缔组织和邻近细胞的膜域的过程。