Patterning of ciliated epithelia by mechanical strain

机械应变对纤毛上皮的图案化

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要纤毛上皮产生对人体器官形成和功能至关重要的定向流体流动。该领域的关键问题之一是这些上皮如何获得平面轴所需的平面轴纤毛的定位或定位，因此以适当的方式指导睫状流。这个问题是在左右模式的背景下，基于流动的机制运行尤其重要在称为左右组织者（LRO）的结构内。 LRO中产生的流量沿着对称性产生左右身体轴和此过程中的缺陷被认为是异性恋的主要原因人类，包括先天性心脏缺陷的病因。为了实现基于流动的图案，纤毛是沿着LRO细胞的前后（A-P）平面轴定位，导致倾斜导致向左流量，但是该轴最初与A-P身体轴对齐是未知的。最近，机械应变具有出现是一种重要的全球提示，它指导上皮中平面极性的轴细胞，提高了机械提示也指导LRO的形成的可能性。确实，在初步研究，发现机械应变不仅是对爪蟾lro的平面轴的模式而且还形成了纤毛和纤毛的位置。机械应变对LRO的影响将是使用成像方法和实验操作进行了研究，这些操纵干扰了菌株的模式胚胎。这些研究将共同提供有关机械应变如何充当的新见解多方面的提示到直接左右轴基于流动图案所需的关键特征，以及如何胚胎中的机械扰动会导致出生缺陷。