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Morphogenesis of the fetal intestinal epithelium

胎儿肠上皮的形态发生

基本信息

批准号：
9177514
负责人：
DEBORAH L. GUMUCIO
金额：
$ 39.77万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-21 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9177514
关键词：
Adherent Culture Adult Anterior Apical Apoptosis Area Automobile Driving Basement membrane Biological Models Birth CASP3 gene CDX2 gene Cell Cycle Cell Nucleus Cell Survival Cell division Cells Cellular biology Cessation of life Data Daughter Defect Development Developmental Biology Diagnosis Dorsal Endoderm Engineering Ensure Epithelial Epithelial Cells Epithelium Erinaceidae Event Exhibits FLNA gene Failure Figs - dietary Filopodia Fingers Foundations Generations Genetic Goals Golgi Apparatus Growth Human Immigration In Vitro Inherited Intestines Label Life Mechanics Mesenchymal Mesoderm Mitosis Mitotic Modeling Molecular Morphogenesis Mus Mutation Nuclear Organ Organoids Pathway interactions Pattern Period Analysis Play Positioning Attribute Process Property Pseudostratified Epithelium Radial Randomized Resolution Role Shapes Short Bowel Syndrome Site Staging Staining method Stains Surface System Techniques Testing Time Tissues Tube Villus Work absorption abstracting base cell type daughter cell driving force ezrin fetal filamin foot human embryonic stem cell improved in vitro Model intercalation intestinal epithelium intestinal villi mathematical model migration monolayer nutrient absorption pressure square foot stem tool transcriptome

项目摘要

Abstract The adult human intestine is over 20 feet long and has a functional absorptive surface area of nearly 2,000 square feet. Three major processes (which take place prior to birth) establish the effective absorptive surface required to sustain life: a) intestinal lengthening; b) generation of villi and c) apical surface polarization. The molecular processes underlying these attributes are important clinically and therapeutically, but are poorly understood. Work in the last project period established a model of intestinal growth, characterized by rapid proliferation, low apoptosis and directional dispersion of cells along the anterior/posterior (A/P) axis. Analysis of Wnt5a null intestines (a short bowel model) revealed defects in extension of radial filopodia during interkinetic nuclear migration, increased apoptosis, reduced pJNK activity, altered Golgi positioning and reduced Filamin A. Aim 1 is driven by the hypothesis that a Wnt5a-Ror2-Filamin A pathway controls radial filopodial extension, insuring cell survival in the epithelium; this is important for proper lengthening. This pathway will be explored using genetic tools and intestinal explant cultures. At E14.5, subepithelial mesenchymal clusters form, causing overlying epithelial cells to change shape. Epithelial cells between clusters activate Cd44v6; rounded mitotic cells in these regions appear to drive a process of rapid invagination that determines the villus domains. The hypothesis driving Aim 2 is that Epithelial invagination defines the apical surfaces of the first villi; this process is driven by patterned mesenchymal clusters and aided by mechanical forces and specialized cell divisions. The role of intra-epithelial pressure and the need for mitotic progression and oriented cell division will be examined; the basis for impeded invagination in Ezrin-/- mice will be investigated. Finally, the cellular and molecular aspects of apical surface polarization and maturation will be studied in the early human endoderm using a new in vitro model system. The hypothesis underlying Aim 3 is: Human congenital short bowel caused by mutations in FLNA and CLMP result in improper apical polarization. The molecular sequence of polarization will be established in cultures of differentiating CDX2 cells and effects of short bowel mutations on that sequence will be determined. By focusing on the cell biology underlying the developmental biology of the early intestine, these studies are unveiling key processes that establish the template for generation of the apical absorptive surface. Mathematical modeling of the data is revealing which parameters are most critical over developmental time.

摘要