The role of lung lipofibroblasts in alveolar differentiation

肺脂肪成纤维细胞在肺泡分化中的作用

• 批准号: 10331843
• 负责人: Michelle D Tallquist
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10331843
• 关键词: Affect; Alveolar; Alveolar Cell; Alveolar Process; Alveolus; Candidate Disease Gene; Cell Differentiation process; Cell physiology; Cells; Chronic lung disease; Communication; Complication; Data; Development; Embryo; Failure; Fibroblasts; Gases; Gene Deletion; Gene Expression Profiling; Goals; Growth Factor; Impairment; In Vitro; Infant; Injury; Knowledge; Lead; Lipids; Lung; Mesenchymal; Mus; Natural regeneration; Organoids; Population; Premature Birth; Premature Infant; Process; Risk; Role; Shapes; Signal Transduction; Time; Ventilator; Vesicle; alveolar type II cell; base; cell type; experimental study; improved; in vivo; lung development; lung maturation; novel therapeutic intervention; novel therapeutics; postnatal; premature lungs; pulmonary function; respiratory distress syndrome; surfactant; surfactant production; surfactant replacement; therapeutic target; transcription factor

Abstract A complication of preterm birth is underdeveloped lungs that lack surfactant and adequate gas exchange due to immature alveoli. Although recent advances have been made, the process of alveolar maturation is not well understood. A goal of this project is to understand signaling from mesenchymal cells that direct alveologenesis, the final stage of lung development. We have found that disruption of a specialized fibroblast, the lipofibroblast, results in reduced type II alveolar cell differentiation. Type II alveolar cells are responsible for surfactant production, and we will investigate the communication between lipofibroblasts and alveolar cells during lung development in the mouse. The lipofibroblast has been a difficult cell to identify, and little is known about the function of these cells. Our preliminary data demonstrate that a transcription factor is required for the development of lipofibroblasts and alveolar differentiation. Based upon these preliminary findings, we hypothesize that lipofibroblasts are required for the later steps of lung development and that they secrete growth factors that are required specifically for terminal differentiation of type II alveolar cells. We will investigate these cellular interactions in two specific aims. In specific aim I, we will determine how lipofibroblasts impact alveolar differentiation by examining the temporal requirement for lipofibroblasts and by evaluating postnatal lung development in mice lacking lipofibroblasts. In Specific Aim II we will use in vitro organoid culture and gene expression profiling to explore the lipofibroblast cellular signals that direct type II alveolar differentiation. Together these aims will define the role of the lipofibroblast and potentially identify therapeutic targets for increasing the rate of type II alveolar differentiation in preterm births.

摘要 早产的一个并发症是肺部发育不全，缺乏表面活性剂和足够的气体 由于不成熟的肺泡。虽然最近取得了进展， 肺泡的成熟还不太清楚。这个项目的一个目标是了解信号 从引导肺泡形成的间充质细胞，肺泡形成是肺发育的最后阶段。我们 已经发现，破坏一种专门的成纤维细胞，脂肪成纤维细胞， 肺泡细胞分化。II型肺泡细胞负责表面活性剂的产生， 我们将研究肺内脂肪成纤维细胞和肺泡细胞之间的通讯， 在老鼠身上的发展脂肪成纤维细胞是一种很难识别的细胞， 了解这些细胞的功能。我们的初步数据表明， 因子是脂肪成纤维细胞和肺泡分化的发育所必需的。基于 根据这些初步的发现，我们假设脂肪成纤维细胞是后期步骤所必需的。 肺发育，并分泌生长因子，特别是需要终端 II型肺泡细胞的分化。我们将分两部分研究这些细胞间的相互作用 具体目标。在具体目标I中，我们将确定脂肪成纤维细胞如何影响肺泡 通过检查脂肪成纤维细胞的时间要求和通过评估 缺乏脂肪成纤维细胞的小鼠的出生后肺发育。在具体目标II中，我们将使用 体外类器官培养和基因表达谱，以探索脂肪成纤维细胞信号 指导II型肺泡分化。这些目标将共同确定 脂肪成纤维细胞，并可能确定治疗靶点，以增加II型肺泡 早产儿的分化。