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Investigating Tight Junction-Mediated Spatial Organization in Polarized Epithelia.

研究极化上皮中紧密连接介导的空间组织。

基本信息

批准号：
9107714
负责人：
Brian Belardi
金额：
$ 5.43万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9107714
关键词：
Actins Adhesions Affect Anabolism Apical Binding Proteins Biology Cadherins Cancerous Carcinoma Cell Polarity Cell membrane Cell physiology Cell surface Cells Chemicals Complex Coupled Custom Cytoplasmic Protein Cytoskeleton Dependence Diffusion Disease Elasticity Electrons Environment Enzymes Epithelial Epithelial Cells Epithelium Exclusion Fluorescence Glycoproteins Goals Integral Membrane Protein Integrins Lateral Lead Link Lipid Bilayers Lipids Maintenance Malignant Neoplasms Mechanics Mediating Membrane Membrane Proteins Mesenchymal Metastatic Carcinoma Methods Microfluidics Modeling Molecular Monitor Mucins Normal Cell Organ Pattern Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositol Phosphates Property Proteins Regulation Role Scanning Probe Microscopes Side Sorting - Cell Movement Spectrum Analysis Structure Techniques Testing Tight Junctions Tissues Tumor Suppression Work apical membrane base basolateral membrane cantilever cell type claudin-1 protein drug development experience fluorescence imaging imaging system insight new therapeutic target optical imaging particle physical property prevent protein complex protein protein interaction public health relevance reconstitution segregation trait tumor progression unilamellar vesicle unnatural amino acids zonula occludens-1 protein

项目摘要

DESCRIPTION (provided by applicant): Asymmetry of epithelial cells is necessary for proper organ function in metazoans and for impeding aberrant epithelial-mesenchymal transition. Epithelial cell membranes are divided into two domains, apical and basolateral, which are demarcated by tight junctions (TJs). These electron dense structures encircle the cell and connect the apices of opposing cells. TJs are thought to maintain cell polarity by limiting the lateral diffusion of domain-specific components, such as the apical, heavily glycosylated mucins. However, the regulation and mechanism of the TJ complex as a barrier remains obscure. This proposal will determine how physical constraints on TJ proteins can drive spatial organization essential for maintaining cell polarity. Transmembrane TJ proteins, e.g. claudin-1, are linked to the actin cytoskeleton through cytosolic TJ proteins, e.g. ZO-1. Recent work has suggested that actin networks and protein size are critical determinants for membrane asymmetry, and as such, we propose that TJs are mechanically regulated. We will examine the effect of force on TJ's ability to prevent translocation of domain-specific phosphatidylinositol phosphates using a patterned cantilever and a custom-built atomic force microscope with a side-view optical imaging system. We will also test whether TJs segregate proteins based on a size-dependent sorting mechanism. This work will provide new insight into how TJs are able to maintain cell polarity and how dysregulation of TJs leads to disease, particularly cancer.