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.

项目总结/摘要 随着每一次吸气、呼气和跨越发育、成熟、衰老和衰老， 在发病机制中，肺持续处于机械张力下。生物物理力是如何 感知和反应的方式仍然知之甚少。在气体交换区， 在这个力的前面，张力分布在广阔的牙槽表面。在这项研究中，我们将 研究的中心前提是机械张力，肺泡上皮细胞， 触发分子反馈回路，驱动气体的产生和再生 交换表面积 在这个反馈回路的中心是压电，这是一个大的膜局部通道， 典型的机械传感器压电基因首先在神经元中被发现和研究， 在肺中广泛表达。我们的初步数据表明，虽然在Piezo基因的损失， 肺间充质或内皮不会导致明显的肺泡结构缺陷， 在肺上皮细胞中失活这些基因，特别是Piezo 2，导致肺泡简化 在出生后早期的肺部。在成人肺中，肺泡上皮中的Piezo 2损失导致 急剧增加对肺泡损伤的敏感性，导致纤维化。在这项研究中，我们将 研究这种机械感觉回路在发育（目标1）和损伤修复中的性质 (Aim 2）。这一发现将推进我们对机械感觉如何调节大小的认识。 和肺泡表面的组成。