Mechanosensor Function in the Control of Gas Exchange Surface Size and Composition

机械传感器在控制气体交换表面尺寸和成分中的功能

• 批准号: 10720855
• 负责人: Xin Sun
• 金额: $ 56.79万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10720855
• 关键词: ATAC-seq; Adult; Aging; Alveolar; Alveolus; Architecture; Area; Biophysics; Birth; Bleomycin; Breathing; Bronchopulmonary Dysplasia; Calcineurin; Calcium; Cations; Cell Fate Control; Cell Nucleus; Cell Size; Cells; Childhood; Chromatin; Cues; Cytoskeleton; Data; Dedications; Development; Diagnosis; Disease; Endothelial Cells; Endothelium; Epithelial Cells; Epithelium; Equilibrium; Exhalation; Failure; Feedback; Fibrosis; Fluorescent in Situ Hybridization; Gases; Generations; Genes; Genetic; Genetic Transcription; Gestational Age; Health; Infant; Inhalation; Injury; Knowledge; Life; Ligands; Longevity; Lung; Lung Capacity; Mechanics; Mediator; Membrane; Mesenchymal; Mesenchyme; Molecular; Natural regeneration; Nature; Neurons; Nuclear; Nuclear Lamina; Organ; Organ Size; Pathogenesis; Periodicity; Peripheral; Piezo 2 ion channel; Piezo ion channels; Predisposition; Premature Birth; Proliferating; Resistance; Role; Saccule structure; Shapes; Signal Transduction; Structural defect; Surface; Technology; Testing; Tissues; Translating; alveolar epithelium; improved; in vivo; injury and repair; lung maturation; mechanical force; mechanotransduction; mutant; pharmacologic; postnatal; postnatal period; reconstruction; regenerative; repaired; respiratory; response; transcriptome sequencing; transcriptomics

PROJECT SUMMARY/ABSTRACT With each inhalation, exhalation and across development, maturation, aging and pathogenesis, the lung is constantly under mechanical tension. How the biophysical force is sensed and responded to remains poorly understood. In the gas exchange region that bears the front of this force, tension is distributed across the vast alveolar surface. In this study, we will investigate the central premise that mechanical tension, sensed by alveolar epithelial cells, triggers a molecular feedback loop that drives the generation and regeneration of the gas exchange surface area. At the center of this feedback loop is Piezo, a large membrane localized channel that is a quintessential mechanosensor. First discovered and studied in neurons, Piezo genes are also widely expressed in the lung. Our preliminary data show that while loss of Piezo genes in the lung mesenchyme or the endothelium did not lead to discernable alveolar structural defects, inactivating these genes, especially Piezo2, in the lung epithelium led to alveolar simplification in the early postnatal lung. In the adult lung, Piezo2 loss in the alveolar epithelium led to drastically increased susceptibility to alveolar damage, leading to fibrosis. In this study, we will investigate the nature of this mechanosensory circuit in development (Aim 1) and injury repair (Aim 2). The findings will advance our knowledge on how mechanosensation could tune the size and composition of the alveolar surface.

项目摘要/摘要 每次吸入，呼气以及整个开发，成熟，衰老和 发病机理，肺部不断在机械张力下。生物物理如何 感觉到并回应仍然很少理解。在带有的气体交换区 该力的正面，张力分布在巨大的牙槽表面。在这项研究中，我们将 研究中心前提，机械张力，肺泡上皮细胞感应， 触发一个分子反馈回路，该回路驱动气体的产生和再生 交换表面积。 在此反馈循环的中心是Piezo，这是一个大膜局部通道 典型的机械传感器。在神经元中首次发现和研究了压电基因也是 在肺中广泛表达。我们的初步数据表明，尽管在 肺间质或内皮没有导致可辨别的肺泡结构缺陷， 在肺上皮中灭活这些基因，尤其是压电2，导致肺泡简化 在产后早期的肺中。在成年肺中，肺泡上皮的压电损失导致 大幅提高了对肺泡损伤的敏感性，导致纤维化。在这项研究中，我们将 研究该机械感应电路的性质（AIM 1）和伤害修复 （目标2）。这些发现将提高我们对机械敏如何调整大小的知识 和肺泡表面的组成。