Developmental processes shaping the luminal surface & stem cell zones in the gut

描述（由申请方提供）：胃肠道的管腔表面沿肠道的解剖学节段沿着具有不同的结构，例如中肠中的胃皱褶、环形皱襞和绒毛以及后肠中的吸器和结肠绒毛。内胚层地形的出现与增殖细胞进入图案化阵列的空间限制相一致，随后将形成隐窝和凹坑。这些上皮干细胞区维持肠的腔褶结构。绒毛萎缩可导致营养不良和脱水，这通常是难治性的;管腔干细胞区结构的破坏是癌症的早期迹象。了解干细胞区的模式和管腔地形是如何相关的，将有助于了解这些疾病。最近，它已被证明，生成的管腔地形的发展小肠可以完全理解的机械力的多轴屈曲。不同轴向平滑肌分化的时间为生长的粘膜提供了足够的物理约束以产生绒毛。这一发现表明，沿沿着消化道的不同形状的褶皱可能是由一些物理参数的变化以及。此外，这一发现表明，通过屈曲的褶皱可以为肠道中的图案化的、受限的上皮干细胞区提供径向不均匀的位置线索。最后，它指出了机械过程在管腔再生条件中的可能作用。为了研究这一点，提出了以下目标：具体目标1。确定物理力在指定沿着肠道前后（A-P）轴的不同内胚层地形中的作用。具体目标2。确定拓扑结构在小肠发育中干细胞区形成和维持中对分子信号传导事件的作用。具体目标3。确定病理损伤后成年肠道上皮恢复过程中物理力的作用。这些研究将联合收割机结合鸡和小鼠系统的独特优势。它们与人体解剖学和肠道发育有着密切的相似性。肠道外植体的机械特性和物理操作的测量将与计算机模拟建模方法相结合，以了解机械力在塑造肠道不同管腔地形中的作用。将利用外植体培养物的药理学和遗传扰动来理解形状和形态发生梯度与干细胞隔室图案化的关系。这项工作可能会给我们的病理条件，如绒毛萎缩的理解一个新的光，但也可能有助于更全面的图片之间的分子和机械力的基础肠道形态发生。

DESCRIPTION (provided by applicant): The luminal surface of the gastrointestinal tract has distinct structures along the anatomical segments of the gut such as the gastric rugae, circular folds and villi in the midgut, and haustra and the colonic villi in the hindgut. The emergence of the endodermal topography coincides with the spatial restriction of proliferating cells into patterned arrays from which crypts and pits will later form. These epithelial stem cell zones maintain the luminal fold structure of the gut. Villous atrophy can lead to malnutrition and dehydration that are often refractory; disruption of the luminal stem cell zone architecture is an early sign of cancers. An understanding of how the patterning of the stem cell zones and luminal topography are related would give insight to these diseases. Recently, it has been demonstrated that the generation of luminal topography of the developing small intestine can be completely understood in terms of multi-axial buckling by mechanical forces. The timing of smooth muscle differentiation in different axis provide sufficient physical constraint to the growing mucosa to generate the villi. This finding suggests that the different shapes of folds along the alimentary canal may arise by variation of a few physical parameters as well. Moreover, the finding suggests that the folds by buckling may provide radially non-uniform positional cues for patterned, restricted epithelial stem cell zones in the gut. Lastly, it points o the possible role of mechanical processes in luminal regeneration conditions. To investigate this, following aims are proposed: Specific Aim 1. Determine the role of physical forces in specifying the different endodermal topographies along the anterior-posterior (A-P) axis of the gut. Specific Aim 2. Determine the role of topology on molecular signaling events in the formation and maintenance of stem cell zones in the developing small intestine. Specific Aim 3. Determine the role of physical forces during the recovery of the adult gut epithelium following pathologic insult. These studies will combine the unique advantages afforded by both chick and mouse systems. They share close similarity to human anatomy and gut development. Measurement of mechanical properties and physical manipulation of gut explants will be combined with in silico modeling approaches to understand the role of mechanical forces in shaping the different luminal topographies of the gut. Pharmacological and genetic perturbations on explant cultures will be utilized to understand the relationship of shape and morphogen gradients to the patterning of the stem cell compartments. The work may give a fresh light on our understanding of pathological conditions such as villous atrophy, but may also contribute to a more comprehensive picture between the molecular and mechanical forces that underlie gut morphogenesis.