Morphogenesis and patterning of the vertebrate gut tube.

脊椎动物肠管的形态发生和模式。

• 批准号: 9808701
• 负责人: Nandan L Nerurkar
• 金额: $ 24.3万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-16 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9808701
• 关键词: Address; Adult; Anterior; Attention; Automobile Driving; Biomechanics; Biophysics; Cell Therapy; Cells; Chick Embryo; Congenital Abnormality; Congenital Disorders; Data; Detection; Development; Digestion; Electroporation; Embryo; Embryology; Embryonic Structures; Endoderm; Endoderm Cell; Epithelial; Epithelium; Event; Fibroblast Growth Factor; Fluorescent in Situ Hybridization; Foundations; Gastrocoele; Gastrointestinal tract structure; Genes; Goals; Health; Heart; Hindgut; Human; In Situ; Intestines; Knowledge; Light; Limb structure; Malignant Neoplasms; Measurement; Mechanics; Midgut; Molecular; Morphogenesis; Movement; Neural tube; Organ; Pathology; Pattern; Prevalence; Primitive foregut structure; Process; Respiration; Respiratory System; Role; Stem cells; Structure; Testing; Time; Tissues; Tube; Work; base; biophysical analysis; cell motility; experimental study; gastrointestinal; in vivo imaging; insight; mathematical methods; mechanical force; migration; progenitor; regenerative therapy; respiratory; segregation; single molecule; somitogenesis; spatiotemporal; stem cell differentiation; stem cell therapy

PROJECT SUMMARY/ABSTRACT The vital functions or respiration and digestion are carried out by organs that arise from an embryonic structure known as the gut tube. Despite its fundamental importance, morphogenesis of the gut tube has been remarkably understudied, particularly when considered alongside concurrent events in the neural tube, heart, limbs, and other tissues of the developing embryo. The purpose of this work is to study how this structure is formed through an integration of biophysical and molecular approaches, with the goal of revealing how progenitor cell movements in the endodermal epithelium are coordinated with differentiation to construct the foregut, midgut, and hindgut through molecular control of mechanical forces. The gut tube, once formed, is a simple epithelial cylinder, yet it arises through spatiotemporally distinct events that separately give rise to the foregut, midgut, and hindgut segments of the tube. These processes are poorly understood, and in particular, how the formation of these three segments are coordinated to form a single continuous tube remains largely unaddressed. Recently, we have turned to the chick embryo to study gut tube morphogenesis, employing live in vivo imaging, electroporation-based gene misexpression, and biomechanical/mathematical approaches to study formation of the hindgut. These studies revealed that much of what was previously assumed from fate mapping studies about gut tube formation may be incomplete, if not incorrect. The present application extends these approaches to study the biophysical role of collective cell movements in foregut morphogenesis, and to elucidate how cells of the presumptive midgut contribute cells to the forming foregut and hindgut. We will perform highly quantitative analyses of cell movements and physical forces in the presumptive foregut and midgut endoderm, and study the emergence of antero-posterior patterning in the context of cell movements along this axis, using single molecule fluorescent in situ detection of established marker genes. Understanding of this critical step in vertebrate development will provide valuable insight into the underlying causes of a broad range of gastrointestinal birth defects. Ultimately, the projects emanating from this work will have important implications for the development of cell-based therapies where directed the differentiation of progenitor cells toward distinct gastrointestinal and respiratory lineages is needed.

项目总结/摘要 呼吸和消化等重要功能是由胚胎发育的器官完成的。 被称为消化管的结构。尽管其基本的重要性，肠管的形态发生一直是 特别是当与神经管，心脏， 四肢和发育中的胚胎的其他组织。这项工作的目的是研究这种结构是如何 通过生物物理和分子方法的整合形成，目的是揭示如何 内胚层上皮中的祖细胞运动与分化相协调， 前肠、中肠和后肠通过机械力的分子控制。 肠管一旦形成，是一个简单的上皮圆柱体，但它是通过时空上不同的 分别产生管的前肠、中肠和后肠段的事件。这些过程 了解甚少，特别是，如何形成这三个部分是协调，以形成一个 单根连续管在很大程度上仍未得到解决。最近，我们转向鸡胚来研究 肠管形态发生，采用活体体内成像，基于电穿孔的基因错误表达， 生物力学/数学方法来研究后肠的形成。这些研究表明， 以前从关于肠管形成的命运绘图研究中假设的可能是不完整的， 不正确.本申请将这些方法扩展到研究集体细胞的生物物理作用。 运动在前肠形态发生，并阐明如何假定中肠细胞贡献细胞， 形成前肠和后肠。我们将对细胞运动和物理行为进行高度定量的分析， 力在推定的前肠和中肠内胚层，并研究出现的前后 使用单分子荧光原位检测，在细胞沿该轴沿着运动的背景下形成图案 已建立的标记基因。 了解脊椎动物发育中的这一关键步骤，将为我们提供有价值的见解， 胃肠道出生缺陷的根本原因。最终，这些项目产生于 这项工作将对基于细胞的治疗的发展具有重要意义， 需要祖细胞向不同的胃肠道和呼吸系统谱系分化。