Role of TGFβ/BMP Antagonism in Regeneration of the Alveolar Epithelium After Lung Injury

TGFβ/BMP 拮抗作用在肺损伤后肺泡上皮再生中的作用

• 批准号: 10165810
• 负责人: Rachel Lynne Zemans
• 金额: $ 52.13万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165810
• 关键词: Address; Adult Respiratory Distress Syndrome; Alveolar; Architecture; BMP4; Binding; Cell Count; Cell Cycle; Cell Cycle Arrest; Cell Differentiation process; Cell Proliferation; Cells; Cessation of life; Coupled; Data; Deposition; Down-Regulation; Epithelial; Epithelial Cells; Failure; Fibroblast Growth Factor; Fibroblasts; Foundations; G1 Arrest; Gases; Genes; Genetic Transcription; Goals; Growth Factor; Homeostasis; Human; In Vitro; Injury; Investigation; Knockout Mice; Link; Lung; Lung diseases; Methods; Molecular; Morphology; Mus; Natural regeneration; Organoids; Pathogenesis; Pathway interactions; Phase; Phenotype; Physiological; Play; Process; Proliferating; Property; Pulmonary Emphysema; Pulmonary Fibrosis; Reporting; Research; Resolution; Respiratory Failure; Rodent; Role; Signal Transduction; Structure; Sum; Surface; System; TP53 gene; Techniques; Testing; Thinness; Time; Transforming Growth Factor beta; Validation; Work; alveolar epithelium; base; beta catenin; epithelium regeneration; experimental study; in vivo; inhibitor/antagonist; injured; lung injury; lung regeneration; new therapeutic target; novel; progenitor; response; restoration; targeted treatment; transcription factor

PROJECT SUMMARY Significance. Many lung diseases, including the acute respiratory distress syndrome, pulmonary fibrosis, and emphysema, result from a failure of the alveolar epithelium to regenerate normally after injury. Unfortunately, no therapies exist to promote lung regeneration, in large part because of our limited understanding of the underlying molecular mechanisms. Regeneration of the alveolar epithelium is orchestrated principally by alveolar type 2 epithelial cells (AEC2s). Surviving AEC2s proliferate to replace lost cells, after which proliferation halts and some AEC2s differentiate into AEC1s to restore normal alveolar architecture and gas exchange function. Historically, investigations of lung regeneration have explored the mechanisms of AEC2 proliferation. The molecular signals that induce a switch from the proliferation phase to the differentiation phase are poorly understood. Hypothesis. Based on our preliminary data, we hypothesize that during regeneration of the alveolar epithelium after lung injury, TGFβ halts AEC2 proliferation whereas deactivation of TGFβ induces BMP- dependent AEC2 to AEC1 differentiation. Research Plan. Aim 1 will test the hypothesis that TGFβ induces the termination of AEC2 cell proliferation during regeneration after lung injury. Aim 2 will test the hypothesis that TGFβ deactivation drives BMP-dependent differentiation during regeneration after lung injury. Mechanisms of epithelial-fibroblast crosstalk during alveolar regeneration will also be examined. Lung injury will be induced in AEC2- and fibroblast-specific gene deficient mice, and proliferation and differentiation will be quantitated using stringent stereologic techniques. In vivo studies will be directly linked to mechanistic experiments in rodent and human AEC2s grown in 2-dimentional and organoid culture. Conclusion. This work will enhance our understanding of fundamental mechanisms of lung regeneration. Specifically, we will investigate the molecular mechanisms underlying the termination of proliferation and initiation of differentiation, coordinated processes that are critical for restoration of normal alveolar structure and function after injury. These studies may identify novel therapeutic targets to accelerate epithelial regeneration during the pathogenesis of diverse lung diseases.

项目概要 意义。许多肺部疾病，包括急性呼吸窘迫综合征、肺纤维化和 肺气肿是由于肺泡上皮在受伤后无法正常再生而引起的。不幸的是，没有 存在促进肺再生的疗法，很大程度上是因为我们对潜在机制的了解有限 分子机制。肺泡上皮的再生主要由 2 型肺泡协调 上皮细胞（AEC2）。存活的 AEC2 增殖以替代丢失的细胞，此后增殖停止并 一些 AEC2 分化为 AEC1 以恢复正常的肺泡结构和气体交换功能。 历史上，肺再生的研究探索了 AEC2 增殖的机制。这 诱导从增殖期转向分化期的分子信号很差 明白了。 假设。根据我们的初步数据，我们假设在肺泡再生过程中 肺损伤后的上皮细胞中，TGFβ 阻止 AEC2 增殖，而 TGFβ 失活则诱导 BMP- 依赖 AEC2 到 AEC1 的分化。 研究计划。目标 1 将检验以下假设：TGFβ 诱导 AEC2 细胞增殖终止 肺损伤后的再生。目标 2 将检验 TGFβ 失活驱动 BMP 依赖性的假设 肺损伤后再生过程中的分化。肺泡内上皮-成纤维细胞串扰的机制 再生也将受到检查。 AEC2 和成纤维细胞特异性基因缺陷会诱发肺损伤 小鼠，增殖和分化将使用严格的体视技术进行定量。体内 研究将与二维生长的啮齿动物和人类 AEC2 的机械实验直接相关 和类器官培养。 结论。这项工作将增强我们对肺再生基本机制的理解。 具体来说，我们将研究增殖终止的分子机制和 分化的启动，协调过程对于正常肺泡结构的恢复至关重要 受伤后的功能。这些研究可能会确定加速上皮再生的新治疗靶点 在多种肺部疾病的发病机制中。

项目成果

Fatal COVID-19 and non-COVID-19 Acute Respiratory Distress Syndrome is Associated with Incomplete Alveolar Type 1 Epithelial Cell Differentiation from the Transitional State Without Fibrosis.

致命的 COVID-19 和非 COVID-19 急性呼吸窘迫综合征与肺泡 1 型上皮细胞从无纤维化过渡状态的不完全分化有关。

• DOI: 10.1101/2021.01.12.426404
• 发表时间: 2021
• 期刊: bioRxiv : the preprint server for biology
• 作者: Ting,Christopher;Aspal,Mohit;Vaishampayan,Neil;Huang,StevenK;Riemondy,KentA;Wang,Fa;Farver,Carol;Zemans,RachelL
• 通讯作者: Zemans,RachelL