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（由应用程序提供）：本研究基于实验室的早期工作，在雏鸡肠道形态发生中建立了物理力的作用。肠道形成的一个关键方面在很大程度上由机械力驱动，这是肠的环的盘绕。 当原始握把的生长速度比附着的背肠系膜生长快时，这种过程就会发生，这是一种弹性的弹性组织，因此沿肠道沿其长度施加了各向同性力。肠盘的紧密度与这种力，因此与肠道和背肠系膜的松弛长度的差异成正比。这是两个尖端的差异增长决定了肠道的循环模式。因此，一个关键问题变成了这些组织的增长率不同的是什么？在AIM 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。阻止BMP2函数会导致循环减少，而多余的BMP活动增加了环的数量和曲率。第一个目标将量化BMP活性对形态计量和生物物理参数的影响。计算建模将用于识别该系统中的关键生物物理确定器。肠道发育的第二个方面也取决于物理力，是肠腔产生绒毛的屈曲。在此过程中，屈曲力是通过限制而产生的 在相邻平滑肌限制膨胀的时候，上皮的生长。在肠道的其他部分（食道，结肠等）中，平滑肌分化的厚度和时机存在显着差异。 AIM 2中的实验确定了平滑肌结构和动力学中这些差异的程度，导致前后肠道的独特上皮形态。将聘请药物来阻止平滑肌分化以测试其需求。形态计量学和生物物理参数将进行测量并输入计算模型，以测试可以在此基础上完全解释上皮形态的程度。