Patterning and Morphogenesis of the Vertebrate Gut

脊椎动物肠道的模式和形态发生

• 批准号: 8092687
• 负责人: CLIFFORD J. TABIN
• 金额: $ 32.54万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8092687
• 关键词: Affect; Architecture; Attention; Automobile Driving; Biological Models; Cell Adhesion Molecules; Cessation of life; Columnar Epithelium; Congenital Abnormality; Congenital Heart Defects; Cues; Development; Developmental Biology; Dorsal; Elasticity; Embryo; Embryonic Development; Epithelial; Event; Extracellular Matrix; Failure; Feedback; Gastrocoele; Gastrointestinal tract structure; Gene Expression; Genes; Genetic Epistasis; Goals; Growth; Heart; Intestines; Lead; Left; Length; Link; Location; Mediating; Mesenchyme; Mesentery; Midgut; Modeling; Morphogenesis; Morphology; Mus; N-Cadherin; Necrosis; Organ; Organogenesis; Pattern; Phase; Phylogenetic Analysis; Play; Process; Production; Property; Randomized; Regulation; Relative (related person); Repression; Right-On; Role; Rotation; Shapes; Side; Signal Transduction; Specific qualifier value; Staging; Structure; Surface; System; Testing; Three-Dimensional Imaging; Time; Transcriptional Regulation; Tube; Visceral; Work; clinically significant; developmental genetics; notch protein; public health relevance; reconstruction; transcription factor

DESCRIPTION (provided by applicant): The goal of this work is to understand the genetic and developmental underpinnings of organ morphogenesis. In this study, we focus on the problem of looping morphogenesis using the developing midgut as a model system. We previously demonstrated that the chirality of gut rotation (i.e. specification of its rotation in a counterclockwise direction) is mediated by changes in the cellular architecture of the dorsal mesentery. We have identified a number of transcription factors asymmetrically expressed in the dorsal mesentery. In the first Aim we will investigate the role each plays in changing the cellular organization within the mesentery as well as examining their cross regulation to understand the transcriptional network controlling this by first step of gut morphogenesis. In our second Aim we will turn our attention to the later steps of gut morphogenesis. We will examine how each subsequent coiling event relates to the initial decision to coil counter clockwise. We will examine the later roles of specific transcription factors in the process. And we will dissect the roles of physical forces and topological constraints in directing the formation of specific loops during midgut organogenesis. PUBLIC HEALTH RELEVANCE: We are studying looping morphogenesis of the gut. Failure in this process results in serious congenital malformations that, if left uncorrected, can lead to blockage of the GI tract, intestinal necrosis and death. There are also broader implications extending to an understanding of cardiac malformations, as looping morphogenesis is not well understood for any tubal organ, and parallels between the primitive gut tube and its dorsal mesentery with early heart tube and its dorsal mesocardium suggest similar biomechanisms may be involved.

描述（由申请人提供）：这项工作的目标是了解器官形态发生的遗传和发育基础。在这项研究中，我们使用发育中的中肠作为模型系统来关注循环形态发生的问题。我们之前证明了肠道旋转的手性（即逆时针方向旋转的规范）是由背侧肠系膜细胞结构的变化介导的。我们已经鉴定出许多在背肠系膜中不对称表达的转录因子。在第一个目标中，我们将研究每种细胞在改变肠系膜内细胞组织中所发挥的作用，并检查它们的交叉调节，以了解通过肠道形态发生的第一步控制这一点的转录网络。在我们的第二个目标中，我们将把注意力转向肠道形态发生的后续步骤。我们将研究每个后续卷绕事件与逆时针卷绕的初始决定如何相关。我们将研究特定转录因子在此过程中的后续作用。我们将剖析物理力和拓扑约束在中肠器官发生过程中指导特定环形成的作用。 公共卫生相关性：我们正在研究肠道的循环形态发生。这一过程失败会导致严重的先天畸形，如果不加以纠正，可能会导致胃肠道阻塞、肠坏死和死亡。对于心脏畸形的理解也有更广泛的意义，因为任何输卵管器官的循环形态发生都还没有被很好地理解，原始肠管及其背侧肠系膜与早期心管及其背侧心膜之间的相似之处表明可能涉及类似的生物机制。