Integrating Forces and Signals in Tissue-Level Patterning of the Developing Digestive Tract

将力和信号整合到发育中消化道的组织水平模式中

• 批准号: 9244822
• 负责人: CLIFFORD J. TABIN
• 金额: $ 35.16万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9244822
• 关键词: Architecture; Automobile Driving; BMP2 gene; Biophysics; Colon; Computer Simulation; Congenital Abnormality; Defect; Development; Dorsal; Elastic Tissue; Epithelial; Epithelium; Esophagus; Gastrocoele; Gastrointestinal tract structure; Generations; Genes; Genetic; Growth; Growth Factor; Hindgut; Intestines; Large Intestine; Lead; Length; Ligands; Light; Maintenance; Measurement; Measures; Mediating; Mesentery; Morphogenesis; Morphology; Nutrient; Pattern; Pharmaceutical Preparations; Primitive foregut structure; Process; Proteins; Quail; Regulation; Role; Shapes; Signal Transduction; Smooth Muscle; Stretching; Structure; System; Testing; Thick; Time; Tissues; Tube; Work; base; biophysical properties; experimental study; mathematical model; mechanical force; public health relevance; receptor; zebra finch

 DESCRIPTION (provided by applicant): This study builds on earlier work in the lab establishing roles for physical forces in chick gut morphogenesis. One critical aspect of gut formation that is largely driven by mechanical forces is the coiling of the loops of the intestine. This process occurs when the primitive gut tube grows faster than the attached dorsal mesentery, an elastic tissue that gets stretched and hence, exerts an isotropic force on the gut tube along its length. The tightness of the coiling of the gut is proportional to this force and hence, to the difference in the relaxed lengths of the gut tube and dorsal mesentery. Thus, the differential growth of the two tissues determines the looping pattern of the gut. A key question thus becomes, what establishes the different in growth rates of these tissues? In Aim 1, we investigate the role of the secreted protein BMP2 in establishing this differential growth. BMP2 is expressed in the developing gut. Blocking BMP2 function causes a decrease in looping, while the excessive BMP activity increases the number and curvature of the loops. The first aim will quantify the effect of BMP activity on morphometric and biophysical parameters. Computational modeling will be used to identify the key biophysical determinants in this system. A second aspect of gut development, that is also dependent on physical forces, is the buckling of the intestinal lumen to generate villi. In this process, buckling forces are generated through confined growth of the epithelium at a time when expansion is constrained by the adjacent differentiating smooth muscle. In other segments of the gut (esophagus, colon, etc.) there are significant differences in the thickness and timing of smooth muscle differentiation. Experiments in Aim 2 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.

 描述（由申请人提供）：这项研究建立在实验室早期工作的基础上，确定了物理力在鸡肠道形态发生中的作用。肠道形成的一个关键方面是肠袢的卷绕，这在很大程度上是由机械力驱动的。 当原始肠管比附着的背侧肠系膜生长得更快时，就会发生这个过程，背侧肠系膜是一种弹性组织，会被拉伸，从而沿肠管的长度对肠管施加各向同性的力。肠盘绕的紧密度与该力成正比，因此也与肠管和背侧肠系膜松弛长度的差异成正比。因此，两种组织的差异生长决定了肠道的循环模式。因此，一个关键问题是，是什么决定了这些组织生长速度的不同？在目标 1 中，我们研究了分泌蛋白 BMP2 在建立这种差异生长中的作用。 BMP2 是 在发育中的肠道中表达。阻断 BMP2 功能会导致循环减少，而过度的 BMP 活性会增加循环的数量和曲率。第一个目标是量化 BMP 活性对形态和生物物理参数的影响。计算模型将用于确定该系统中的关键生物物理决定因素。肠道发育的第二个方面也依赖于物理力量，即肠腔弯曲以产生绒毛。在此过程中，屈曲力是通过受限产生的 当扩张受到邻近的分化平滑肌的限制时，上皮的生长。在肠道的其他部分（食道、结肠等），平滑肌分化的厚度和时间存在显着差异。目标 2 中的实验确定了平滑肌结构和动力学的这些差异在多大程度上导致了前肠和后肠的不同上皮形态。将使用药物来阻止平滑肌分化以测试其必要性。将测量形态学和生物物理参数并将其输入计算模型，以测试在此基础上可以完全解释上皮形态的程度。