Patterning and Morphogenesis of the Vertebrate Gut

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。在本研究中，我们以发育中的中肠为模型系统，重点研究了环状形态发生的问题。我们先前证明，肠旋转的手性(即其逆时针方向旋转的规范)是由背侧肠系膜细胞构筑的变化所调节的。我们已经鉴定出许多转录因子在背侧肠系膜不对称表达。在第一个目标中，我们将研究它们在改变肠系膜细胞组织中所起的作用以及它们的交叉调节，以了解通过肠道形态发生的第一步控制这一过程的转录网络。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的绕线事件与最初的逆时针绕线决策之间的关系。我们将研究特定转录因子在这一过程中的后续作用。我们还将剖析物理力和拓扑约束在指导中肠器官发生过程中特定环的形成中的作用。 与公共健康相关：我们正在研究肠道的环状形态发生。这一过程的失败会导致严重的先天性畸形，如果不加以纠正，可能会导致胃肠道堵塞、肠道坏死和死亡。对心脏畸形的理解也有更广泛的意义，因为对任何输卵管器官来说，环状形态发生都不是很清楚，原始肠管及其背侧肠系膜与早期心管及其背侧系膜之间的相似之处表明可能涉及类似的生物力学机制。

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.