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Signals and mechanical forces controlling radial gut morphogenesis

控制径向肠道形态发生的信号和机械力

基本信息

批准号：
10684660
负责人：
CLIFFORD J. TABIN
金额：
$ 35.02万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684660
关键词：
Address Agonist Anatomy Architecture Biochemical Biophysics Characteristics Chick Chick Embryo Computer Models Congenital Abnormality Defect Development Dimensions Disparate Embryonic Development Environment Epithelium Equilibrium Erinaceidae Esophagus Event Experimental Models Family Fiber Fingers Gastrocoele Gastrointestinal tract structure Gene Expression Profiling Generations Genes Genetic Genetic Transcription Growth Hindgut In Situ Hybridization Large Intestine Lead Link Location Measures Mechanics Mesenchyme Mesoderm Microdissection Midgut Molecular Morphogenesis Morphology Mucous Membrane Muscle Muscle Fibers Organ Pathway interactions Pattern Pharmaceutical Preparations Play Primitive foregut structure Property Radial Retroviral Vector Role Series Shapes Signal Transduction Small Intestines Smooth Muscle Specific qualifier value Stress Structure Surface System Testing Thick Time Tissue Recombination Tissues Tube Undifferentiated Variant Villus Work antagonist biophysical properties experience experimental study in vivo insight intestinal villi mathematical model mechanical force morphogens nutrient absorption programs transcription factor transcription factor USF

项目摘要

PROJECT SUMMARY/ABSTRACT The midgut is characterized by a series of concentric, mesodermally-derived layers of smooth muscle and mucosa, surrounding an inner, endodermally-derived epithelium. In the mature gut, this epithelium forms finger-like projections extending into the lumen, called villi. In the developing chick, intestinal villi are generated in a step-wise manner, through a series of epithelial buckling events. Buckling forces are generated through the confined growth of the epithelium at a time when expansion is restricted by the adjacent differentiating smooth muscle. The physical constraint experienced by the epithelium changes over time as different layers of smooth muscle are established sequentially. The location of these smooth muscle layers is established through the activity of gradients of Shh and Bmp, which, respectively, have positive and negative effects on smooth muscle differentiation. As they form, the orientation of the fibers in each muscle layer depends upon the mechanical environment of the gut at the time the layer undergoes differentiation. In spite of this general outline of how the midgut architecture is established, there is a dearth of information regarding the tissue-level construction of the other gut segments. Both the foregut and the hindgut arise from the same linear primative gut tube as the midgut, and have the same general concentric organization. However, there are significant differences in the thickness and timing of smooth muscle differentiation in the different gut segments, and the epithelial lining differs dramatically in the three segments. In Aim 1, the mechanisms responsible for the distinct characteristics of the muscle layers in the fore- and hindgut will be elucidated. The signaling systems known to be responsible for defining the location and thickness of the smooth muscle in the midgut will be examined in the fore- and hindgut segments qualitatively (by in situ hybridization) as well as quantitatively (by qPCR) to determine how they differ in expression from the midgut. These signals will be manipulated by electoration in vivo and through culturing with agonists and antagonists in explant culture and utilizing tissue recombination to test their roles functionally. Experiments in Aim 2 will determine the extent to which these differences in smooth muscle architecture and dynamics are responsible for the distinct epithelial morphology of the fore-and hind guts. Drugs will be employed to block smooth muscle differentiation to test their necessity. Morphometric and biophysical parameters will be measured and entered into computational models to test the degree to which epithelial morphology can be entirely explained on this basis. Finally, in Aim 3 we will assess how transcription factors of the Hox and paraHox clusters, known to specify regional identity within the gut, alter the molecular and physical parameters that differentiate the fore-, mid- and hindgut, thereby connecting regional patterning to morphogenesis of the gut. To that end, transcription fctors involved in regional identity will be misexpressed ustilizing retroviral vectors, and changes in biochemical and mechanical parameters will be examined.

项目总结/文摘