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Role of Membrane Trafficking in Epithelial Homeostasis

膜运输在上皮稳态中的作用

基本信息

批准号：
10796580
负责人：
HEIKE FOLSCH
金额：
$ 1.77万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10796580
关键词：
Apical Area Biochemistry Biological Cell Adhesion Molecules Cell Polarity Cell membrane Cell physiology Cells Chronic Clathrin Adaptors Complement Complex Crohn&apos s disease Development Disease Disseminated Malignant Neoplasm Elements Endosomes Epithelial Cells Epithelium Focal Adhesions Growth Growth Hormone Receptor Health Homeostasis Human Human body Imaging Techniques Inflammation Lipids Maintenance Malignant Neoplasms Mass Spectrum Analysis Membrane Nutrient Organ Organizational Change Phosphotransferases Play Polycystic Kidney Diseases Process Proteins Receptor Signaling Recycling Research Role Sorting Speed Surface TLR3 gene Testing Tissues Total Internal Reflection Fluorescent Vesicle Waste Products Work basolateral membrane cell motility experimental study human disease innovation insight migration monolayer novel novel strategies phosphoinositide-3,4,5-triphosphate photoactivation prevent receptor recruit trafficking uptake wound

项目摘要

Epithelial cells play critical roles in many organs and are responsible for elemental processes such as nutrient uptake and waste product secretion. To fulfill these functions, they polarize their plasma membrane into apical and basolateral domains. To maintain tissue homeostasis, epithelial cells must continuously sort newly synthesized and internalized surface receptors to the correct target domain. And after tissue damage, epithelial cells must correctly migrate into the wound and re-colonize the wound area. Loss of polarity is associated with numerous diseases including metastatic cancer, polycystic kidney disease, and Crohn’s disease. How epithelial cell polarity is regulated is thus an important cell biological question with profound implications for human health. Our work identified the epithelial cell-specific clathrin adaptor complex AP-1B as crucial for polarized recycling of cargos to the basolateral domain. Cargos that depend on AP-1B for basolateral localization include important signaling receptors such as epidermal growth hormone receptor whose missorting to the apical domain has been implicated in cancer and polycystic kidney disease, and toll-like receptor 3 whose missorting results in chronic inflammation. A major unresolved question in the field is how AP-1B uniquely functions in epithelial cells, and why its close cousin AP-1A mostly fails to substitute. Our previous work suggested that AP-1B changes the organization of recycling endosomes (REs) to accommodate AP-1B’s function in basolateral sorting. Only AP- 1B but not AP-1A localizes in REs where it triggers the formation of a lipid domain enriched in PI(3,4,5)P3, and facilitates the recruitment of accessory factors including a vesicle-tethering complex (the exocyst) and a lipid kinase (PIPKIg-90). We recently showed that AP-1B expression reduced the speed of collective cell migration after monolayer wounding, a novel function independent of basolateral sorting. We will test the central hypothesis that AP-1B plays dual roles in establishment and maintenance of epithelial monolayers by 1) directing cargos to the basolateral membrane by generating a sorting platform in REs at steady-state and 2) during cell migration by modulating the availability of focal adhesion molecules at the plasma membrane. We will test this hypothesis in our proposed experiments by using state-of-the-art imaging techniques including live TIRF microscopy in combination with photoactivation and unbiased screens including BioID and mass spectrometry to complement innovative cell biological and biochemistry approaches to: 1. Determine how AP-1B generates a basolateral sorting platform, and 2. Determine how AP-1B controls cell migration. Our studies will define new mechanisms governing the organization of polarized epithelial cells at steady-state and during cell migration.

上皮细胞在许多器官中起着至关重要的作用，并负责营养等元素过程