Morphogenesis of the fetal intestinal epithelium

胎儿肠上皮的形态发生

基本信息

批准号：
8666637
负责人：
DEBORAH L. GUMUCIO
金额：
$ 40.73万
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 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8666637
关键词：
Apical Apoptosis Area Back Biomedical Engineering Cell Cycle Cell Nucleus Cell Polarity Cell Shape Cell division Cells Characteristics Columnar Cell Data Defect Development Diagnosis Epithelial Epithelium Event Failure Fetus Fingers Funding Gastrocoele Genetic Goals Growth Height Hour Imaging Techniques Individual Infant Intestines Investigation Knockout Mice Length Life Membrane Mesenchymal Mitosis Modeling Molecular Morphogenesis Mus Newborn Infant Nuclear Nutrient Outcome Study Pattern Phase Phenotype Play Positioning Attribute Process Production Proteins Pseudostratified Epithelium Radial Role S Phase Series Shapes Short Bowel Syndrome Signal Transduction Small Intestines Staging Surface Testing Therapeutic Thick Thinking Time Tissues Tube Villus Work absorption advanced system daughter cell design fetal in utero insight intercalation intestinal epithelium mathematical model migration mouse model novel progenitor reconstruction research study

项目摘要

DESCRIPTION (provided by applicant): The epithelium of the small intestine undergoes a remarkable series of morphogenic changes during its development. The endodermally derived epithelial tube is initially comprised of a single layer of short columnar cells. Between E10.5 and E14.5, the tube increases in girth and length. In the 48 hours between E14.5 and E16.5, the epithelium is dramatically remodeled and the previously flat luminal surface is converted into villi (fingerlike projections of the epithelial surface). Since villi represent the functional absorptive unit of the intestine, a detailed understanding of the mechanisms leading to their formation is an important goal. Moreover, failure to establish proper intestinal surface area (as in idiopathic short bowel syndrome) can be life threatening. Data presented here challenge current thinking about the organization of the early intestinal epithelium and the mechanisms by which the epithelium is remodeled at E14.5. The Working Model underlying this work is that: The early intestinal epithelium (E12.5-14.5) is pseudostratified and grows via symmetrical cell divisions called g-divisions (because they increase epithelial girth and length). At E14.5, luminal surface area is extended by means of a different type of specialized cell division, called e-divisions (because they serve to expand the luminal surface). In e-divisions, new apical surface is added at the cytokinetic furrow. E-divisions therefore separate daughter cells onto different villi. After e-divisions, postmitotic cells change shape, shortening along their apical/basal axis and increasing their apical surface, as the first villi emerge. This cell reshaping rapidly converts epithelial girth to length. The fidelity of these processes requires Wnt5a and planar cell polarity signaling. None of these aspects of intestinal growth have previously been investigated. This proposal makes use of genetic mouse models, a novel intestinal explant culture system and advanced imaging techniques to mechanistically dissect the interconnected signaling and patterning events involved in these surface-generating processes. The Specific Aims are designed to examine the morphological and functional characteristics of g-divisions (Aim 1) and e-divisions (Aim 2) and to investigate the mechanisms underlying intestinal lengthening, including the role of Wnt5a and planar cell polarity signaling (Aim 3). Using all of these data, a mathematical model will be generated to further investigate the role of such parameters as progenitor cycling time, apoptosis and cell shape change in intestinal lengthening. The outcome of these studies could have important implications for the bioengineering of fetal intestinal tissue and the treatment of short bowel syndrome in the fetus and newborn.

描述（由申请人提供）：小肠上皮在其发育过程中经历了一系列显着的形态发生变化。内胚层衍生的上皮管最初由单层短柱状细胞组成。在 E10.5 和 E14.5 之间，管的周长和长度增加。在 E14.5 和 E16.5 之间的 48 小时内，上皮发生显着重塑，之前平坦的管腔表面转变为绒毛（上皮表面的指状突起）。由于绒毛代表肠道的功能吸收单位，因此详细了解其形成机制是一个重要目标。此外，未能建立适当的肠道表面积（如特发性短肠综合征）可能会危及生命。这里提供的数据挑战了当前关于早期肠上皮组织和 E14.5 上皮重塑机制的想法。这项工作的工作模型是：早期肠上皮 (E12.5-14.5) 是假复层的，通过称为 g 分裂的对称细胞分裂生长（因为它们会增加上皮周长和长度）。在 E14.5 中，管腔表面积通过不同类型的专门细胞分裂（称为 e 分裂）来扩展（因为它们用于扩大管腔表面）。在 e-division 中，新的顶端表面被添加到细胞因子沟槽处。因此，电子分裂将子细胞分离到不同的绒毛上。经过电子分裂后，有丝分裂后细胞会改变形状，随着第一个绒毛的出现，沿其顶轴/基轴缩短并增加顶面。这种细胞重塑迅速将上皮周长转化为长度。这些过程的保真度需要 Wnt5a 和平面细胞极性信号传导。肠道生长的这些方面以前都没有被研究过。该提案利用遗传小鼠模型、新型肠道外植体培养系统和先进的成像技术来机械地剖析这些表面生成过程中涉及的相互关联的信号传导和模式事件。具体目标旨在检查 g 分裂（目标 1）和 e 分裂（目标 2）的形态和功能特征，并研究肠道延长的机制，包括 Wnt5a 和平面细胞极性信号传导的作用（目标 3））。利用所有这些数据，将生成一个数学模型，以进一步研究祖细胞循环时间、细胞凋亡和细胞形状变化等参数在肠道延长中的作用。这些研究的结果可能对胎儿肠道组织的生物工程以及胎儿和新生儿短肠综合征的治疗产生重要影响。