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Endocytic Regulation of Intestinal Development

肠道发育的内吞调节

基本信息

批准号：
9262626
负责人：
Jean M Wilson
金额：
$ 41.47万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9262626
关键词：
AMOT gene Adult Animals Apical Architecture Binding Biological Models Brush Border CRISPR/Cas technology Cell Differentiation process Cell Line Cell Proliferation Cell membrane Complex Cytoplasmic Tail Data Development Disease Drosophila genus Endocytosis Endosomes Enterocytes Epithelial Epithelial Cells Epithelium Extracellular Domain Genes Goals Growth and Development function Hand Human In Vitro Integral Membrane Protein Intestinal Diseases Intestinal Mucosa Intestines Knock-out Knockout Mice Knowledge Laboratories Maintenance Mammals Mediating Membrane Membrane Glycoproteins Membrane Proteins Microscopy Modeling Monomeric GTP-Binding Proteins Morphogenesis Neonatal Pathway interactions Pattern Play Positioning Attribute Proteins Recruitment Activity Regulation Resolution Role Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Protein Sorting - Cell Movement Testing Tight Junctions Transcription Coactivator Transcriptional Regulation Villus WNT Signaling Pathway Work Zebrafish apical membrane endotubin experimental study human disease insight intestinal epithelium intestinal homeostasis neonate notch protein occludin scaffold therapeutic target tool trafficking

项目摘要

Endocytic regulation of intestinal development The intestinal mucosa is a highly differentiated epithelial barrier that is fundamental for normal function of the intestine. Vesicular trafficking is now recognized as an essential regulator of epithelial polarity, integrity and cell differentiation, and studies in model systems have shown that endocytosis and membrane trafficking are essential for normal ontogenesis of the intestine. During development, the epithelial cells of the intestine go through an intensely endocytic stage that precedes the acquisition of mature intestinal architecture. We identified endotubin (EDTB) as a highly conserved integral membrane protein in the endocytic complex of the developing intestine. In vitro, EDTB regulates tight junction assembly and contact-mediated inhibition of proliferation. In addition, it binds the small GTPase Rab14, which regulates trafficking between endosomes and the apical plasma membrane. However the role of EDTB during development is completely unknown. We have generated an intestinal epithelial cell-specific EDTB knockout mouse and, in Preliminary Data, show that EDTB knockout early in development results in aberrant ontogenesis of the neonatal intestine, including loss of the apical endocytic complex, intracellular accumulation of apical plasma membrane proteins, and an aberrant brush border. We will use this EDTB conditional knockout mouse, together with enteroid cultures and cell lines, to identify the mechanistic basis for these changes in epithelial differentiation. We will define the mechanisms for interaction with tight junction proteins and define the domains of EDTB that mediate its effects. Also, we will analyze the role of Rab14 using intestinal enteroid cultures and human intestinal epithelial cell lines. Finally, we will examine the signaling pathways known to impact intestinal differentiation and define their interaction with EDTB and apical endosomes. Collectively, these studies will provide insight into the cellular mechanisms of intestinal development, which is essential for our understanding of intestinal function. When completed, the experiments outlined in this proposal will define the role of vesicular trafficking in normal growth, development, and homeostasis of the intestinal epithelium. This fundamental knowledge will have implications for our understanding of intestinal disease, both in neonates and adults, and could lay the groundwork for therapeutic targets.

肠道发育的内吞调节