Patterning of ciliated epithelia by mechanical strain

机械应变对纤毛上皮的图案化

• 批准号: 9354572
• 负责人: Christopher Robert Kintner
• 金额: $ 40.26万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9354572
• 关键词: Affect; Anterior; Apical; Automobile Driving; Cells; Cilia; Congenital Abnormality; Congenital Heart Defects; Cues; Defect; Development; Down-Regulation; E-Cadherin; Embryo; Embryonic Development; Epithelial; Epithelial Cells; Epithelium; Etiology; Gene Expression; Genetic Transcription; Human; Lead; Left; Length; Life; Location; Mechanics; Mediating; Microtubules; Modeling; Organ; Pathway interactions; Pattern; Play; Positioning Attribute; Process; Reproducibility; Role; Sensory; Signal Pathway; Signal Transduction; Situs Inversus; Skin; Structure; Testing; Time; Tissues; Transforming Growth Factor beta; Xenopus; base; beta catenin; cell motility; cell type; cilium motility; experience; fluid flow; gastrulation; imaging approach; in vivo; insight; intercalation; notch protein; novel; planar cell polarity; postnatal; response; transcriptome sequencing; treatment effect

Project Summary Ciliated epithelia produce directed fluid flow that is critical for human organ formation and function. One of the key outstanding questions in the field is how these epithelia acquire a planar axis required for cilia orientiation or positioning, thus directing ciliary flow in an appropriate way for function. This issue is particularly important in the context of the left-right patterning, where a flow-based mechanism operates within a structure called the left-right organizer (LRO). Flow produced in the LRO breaks symmetry along the left-right body axis, and defects in this process is thought to be a leading cause of heterotaxy in humans, including in the etiology of congenital heart defects. To achieve flow-based patterning, cilia are positioned along the anterior-posterior (A-P) planar axis of LRO cells, causing a tilt that results in leftward flow but how this axis is initially aligned to the A-P body axis is unknown. Recently, mechanical strain has emerged as an important global cue that directs the axis of planar polarity in epithelia with multiciliated cells, raising the possibility that mechanical cues also direct the formation of the LRO. Indeed, in preliminary studies, mechanical strain was found to not only pattern the planar axis of the Xenopus LRO, but also the formation of motile cilia, and cilia location. The impact of mechanical strain on the LRO will be studied using imaging approaches and experimental manipulations that perturb the patterns of strain in the embryo. Together, these studies will provide new insights into how mechanical strain can act as a multifaceted cue to direct key features required for flow-based patterning of the left-right axis, and how mechanical perturbations in the embryo can lead to birth defects.

项目概要 纤毛上皮产生定向流体流动，这对于人体器官的形成和功能至关重要。 该领域的关键悬而未决的问题之一是这些上皮细胞如何获得所需的平面轴 纤毛定向或定位，从而以适当的方式引导纤毛流动以实现功能。这个问题是 在基于流程的机制运行的左右模式背景下尤其重要 在称为左右组织器（LRO）的结构中。 LRO 中产生的流动打破了对称性 左右身体轴，这个过程中的缺陷被认为是异型性的主要原因 人类，包括先天性心脏病的病因学。为了实现基于流动的图案，纤毛是 沿 LRO 细胞的前后 (​​A-P) 平面轴定位，导致倾斜，导致向左 但该轴最初如何与 A-P 体轴对齐尚不清楚。最近，机械应变已 成为一个重要的全局线索，指导具有多纤毛的上皮细胞的平面极性轴 细胞，这增加了机械信号也指导 LRO 形成的可能性。确实，在 初步研究发现，机械应变不仅影响了非洲爪蟾 LRO 的平面轴， 还能形成活动的纤毛，以及纤毛的位置。机械应变对 LRO 的影响为 研究使用成像方法和实验操作扰乱应变模式 胚胎。总之，这些研究将为机械应变如何充当 用于指导左右轴基于流的图案化所需的关键特征的多方面提示，以及如何 胚胎中的机械扰动可能导致出生缺陷。