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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要随着每一次吸气、呼气以及整个发育、成熟、衰老和发病机制中，肺始终处于机械张力之下。生物物理力是怎样的感知和响应仍然知之甚少。在承载着的气体交换区域在该力的前面，张力分布在广阔的肺泡表面。在本研究中，我们将研究中心前提，即肺泡上皮细胞感知的机械张力，触发分子反馈回路，驱动气体的产生和再生交换表面积。该反馈环路的中心是压电，一个大型膜局部通道，它是典型的机械传感器。压电基因首先在神经元中发现和研究广泛表达于肺中。我们的初步数据表明，虽然压电基因的损失肺间质或内皮细胞不会导致可辨别的肺泡结构缺陷，使肺上皮中的这些基因（尤其是 Piezo2）失活会导致肺泡简化在产后早期的肺部。在成人肺中，肺泡上皮细胞中 Piezo2 的缺失导致显着增加肺泡损伤的易感性，导致纤维化。在本研究中，我们将研究发育（目标 1）和损伤修复中这种机械感觉回路的性质（目标 2）。这些发现将增进我们对机械感觉如何调整尺寸的认识和肺泡表面的组成。