Understanding Vangl2-mediated mesenchymal thinning during lung sacculation

了解肺囊化过程中 Vangl2 介导的间质变薄

• 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
• 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

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.

项目摘要 大多数早产发生在肺处于胚胎发育的最后阶段， 囊状然而，我们对远端肺的精细结构在此期间如何发展的理解， 阶段非常稀少，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）途径最近已被证明发挥作用， 在囊状形成中起关键作用，囊状形成是一个发育过程，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充质变薄。在脊椎动物中，五氯苯酚途径调节 在关键的发育过程中，如原肠胚形成和神经管关闭的收敛延伸。我 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 基因Vang 12在肺间质中是实现正常囊状形成所特别需要的。我 假设Vangl 2调节细胞骨架机制，以平行于 会聚延伸的夹层是如何拉长体轴的。验证这一假设将支持 模型中，肺间充质中的细胞重排积极塑造远端肺， 并将描绘一种新的间充质PCP途径。为了验证这一假设，我将确定 Vangl 2在囊状形成过程中通过肝- 使用转基因小鼠的成像方法（Aim 1）。然后我将使用遗传和生化联合方法， 绘制Vangl 2驱动这种间充质特异性过程的分子参与者（Aim 2）。 成功地完成这些目标将加深我们对Vangl 2在细胞内和细胞外功能的理解。 和分子水平促进肺发育期间间充质形态的显著变化。 此外，他们还将首次阐明，一个特定的机制，间充质变薄，在 囊状这些知识不仅将为未来的治疗研究提供信息， 补充Vangl 2功能，以治疗出生时肺部严重发育不全的早产儿，但也将 阐明了可能证明在工程化肺组织中有用的发育途径， 呼吸条件。