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.

项目摘要 纤毛上皮细胞产生定向的流体流动，这对人体器官的形成和功能至关重要。 该领域的一个关键的悬而未决的问题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 这在左右模式的上下文中尤其重要，其中基于流的机制起作用 在一个叫做左右组织者（LRO）的结构中。在LRO中产生的流动破坏对称性，沿着 左-右身体轴，这个过程中的缺陷被认为是异位的主要原因， 人类，包括先天性心脏缺陷的病因学。为了实现基于流动的图案化， 沿着LRO细胞的前后（A-P）平面轴沿着定位，导致倾斜，导致倾斜 但是该轴最初如何与A-P身体轴对齐是未知的。最近，机械应变 出现作为一个重要的全球线索，指导轴的平面极性在上皮细胞与多纤毛 细胞，提高了机械线索也指导LRO形成的可能性。的确，在 初步研究发现，机械应变不仅能使爪蟾LRO的平面轴形成图案， 而且还涉及运动纤毛的形成和纤毛的定位。机械应变对LRO的影响将是 使用成像方法和实验操作研究，这些方法扰乱了 胚胎总之，这些研究将提供新的见解，如何机械应变可以作为一个 多方面的线索，以指导左右轴的流动模式所需的关键特征，以及如何 胚胎中的机械扰动可能导致出生缺陷。