Understanding Vangl2-mediated mesenchymal thinning during lung sacculation

了解肺囊化过程中 Vangl2 介导的间质变薄

基本信息

批准号：
10495188
负责人：
Sarah Virginia Paramore
金额：
$ 2.36万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10495188
关键词：
Affect Architecture Area Biochemical Biomedical Engineering Birth Cell Polarity Cell Shape Cell physiology Cells Cilia Complex Data Defect Development Developmental Process Disease Distal Embryo Engineering Epithelial Epithelial Cells Future Gases Genes Genetic Genetic study Goals Image Infant Integral Membrane Protein Intercellular Junctions Joints Knock-out Knowledge Lead Limb structure Lung Lung diseases Maps Mass Spectrum Analysis Mediating Mesenchymal Mesenchyme Modeling Molecular Morphogenesis Morphology Movement Neonatal Neural Tube Closure Newborn Infant Outcome Pathway interactions Phenocopy Play Premature Birth Premature Infant Process Proteins Reporting Research Research Personnel Respiratory Disease Role Saccule structure Shapes Slice Structure of parenchyma of lung Surface Testing Therapeutic Intervention Thick Thinness Time Tissues Transgenic Mice Trees Vertebrates Work airway epithelium convergent extension gastrulation imaging approach insight intercalation lung development mouse genetics mutant novel planar cell polarity programs respiratory

项目摘要

Project Summary The majority of preterm births occur while the lungs are in their final embryonic developmental stage, sacculation. However, our understanding of how the delicate architecture of the distal lung develops during this stage is extremely sparse, limiting our capacity to develop therapeutic interventions for neonatal infants affected by respiratory diseases. The planar cell polarity (PCP) pathway has recently been shown to play a pivotal role in sacculation, a developmental process during which the epithelial surface area of distal airways expands while the mesenchyme between adjacent airways thins. In vertebrates, the PCP pathway regulates convergent-extension during key developmental processes such as gastrulation and neural tube closure. My preliminary data reveal that, although epithelial PCP is not required for lung morphogenesis, the core PCP gene Vangl2 is specifically required in the pulmonary mesenchyme to achieve normal sacculation. I hypothesize that Vangl2 regulates cytoskeletal machinery to drive mesenchymal thinning in a way that parallels how convergent-extension intercalations elongate the body axis. Confirming this hypothesis would support a model in which cell rearrangements in the pulmonary mesenchyme actively shape the distal lung during sacculation and would delineate a novel mesenchymal PCP pathway. To test this hypothesis, I will determine the cellular mechanisms by which Vangl2 promotes mesenchymal thinning during sacculation through a live- imaging approach using transgenic mice (Aim 1). I will then use a joint genetic and biochemical approach to map the molecular players through which Vangl2 drives this mesenchyme-specific process (Aim 2). Successfully completing these aims will deepen our understanding of how Vangl2 functions at both the cellular and molecular level to facilitate dramatic changes in mesenchyme morphology during lung development. Moreover, they will elucidate, for the first time, a specific mechanism for mesenchymal thinning during sacculation. This knowledge will not only inform future research into therapies that may enhance or supplement Vangl2 function to treat preterm infants born with severely underdeveloped lungs, but will also illuminate a developmental pathway that may prove useful in engineering lung tissues to treat additional respiratory conditions.

项目概要大多数早产发生在肺部处于胚胎发育的最后阶段时，囊肿。然而，我们对远端肺的微妙结构在此过程中如何发育的理解阶段极其稀疏，限制了我们为新生儿开发治疗干预措施的能力受呼吸道疾病影响。平面细胞极性（PCP）通路最近被证明发挥着重要作用在囊化中发挥关键作用，囊化是一种发育过程，在此过程中远端气道的上皮表面积扩张，而相邻气道之间的间质变薄。在脊椎动物中，PCP 途径调节原肠胚形成和神经管闭合等关键发育过程中的聚合延伸。我的初步数据显示，虽然上皮 PCP 不是肺形态发生所必需的，但核心 PCP 肺间质特别需要基因 Vangl2 来实现正常的球囊化。我假设 Vangl2 调节细胞骨架机制以平行的方式驱动间充质变薄会聚延伸插层如何拉长身体轴线。证实这一假设将支持模型中，肺间充质中的细胞重排主动塑造远端肺囊泡并描绘出一种新的间充质 PCP 途径。为了检验这个假设，我将确定 Vangl2 通过活细胞机制在囊化过程中促进间充质变薄使用转基因小鼠的成像方法（目标 1）。然后我将使用联合遗传和生化方法绘制 Vangl2 驱动这一间充质特异性过程的分子参与者（目标 2）。成功完成这些目标将加深我们对 Vangl2 如何在细胞和细胞中发挥作用的理解。和分子水平，以促进肺发育过程中间充质形态的巨大变化。此外，他们将首次阐明间充质变薄的具体机制。囊肿。这些知识不仅将为未来可能增强或增强治疗的研究提供信息。补充Vangl2功能可以治疗出生时肺部严重发育不良的早产儿，但也将阐明了一条可能被证明有助于改造肺组织以治疗其他疾病的发育途径呼吸系统状况。