Functions of specialized pulmonary endothelial cell types in regeneration of the lung

特殊肺内皮细胞类型在肺再生中的功能

• 批准号: 10300987
• 负责人: Terren Kathryn Niethamer
• 金额: $ 6.89万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300987
• 关键词: AGTR2 gene; Acute; Acute Lung Injury; Adult; Alveolar; Alveolar Cell; Alveolus; Architecture; Bioinformatics; Biology; Biomedical Research; Blood; Blood Vessels; Blood capillaries; Brain; Capillary Endothelial Cell; Carbon Dioxide; Cardiovascular system; Cause of Death; Cell Lineage; Cells; Chronic Disease; Data; Development; Disease; Distal; Endothelial Cells; Endothelium; Environment; Ephrins; Epithelial; Epithelial Cells; Equilibrium; Fibrosis; Flow Cytometry; Fluorescence-Activated Cell Sorting; Future; Gases; Gene Expression Profile; Heart; Heterogeneity; Homeostasis; Immunohistochemistry; Individual; Infection; Influenza; Injury; Institution; Intestines; Knowledge; Life; Lung; Lung diseases; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Mesenchymal; Methods; Modeling; Morphogenesis; Mus; Natural regeneration; Organ; Organoids; Oxygen; Patients; Pattern; Pennsylvania; Play; Population; Process; Proliferating; Pulmonary alveolar structure; Regenerative Medicine; Research; Research Personnel; Research Training; Resolution; Resources; Role; Shapes; Signal Pathway; Signal Transduction; Signaling Molecule; Skin; Structure; System; Time; Tissues; Training; Universities; Work; alveolar epithelium; body system; career; cell regeneration; cell type; differential expression; genomic data; improved; in vivo; influenzavirus; injured; injury and repair; lung injury; lung regeneration; notch protein; prevent; progenitor; regeneration potential; regenerative; repaired; response to injury; single cell analysis; single-cell RNA sequencing; stem cells; transcription factor; transcriptome sequencing

Project Summary The lung possesses a low rate of cellular turnover at homeostasis but contains facultative stem cells that can be activated to regenerate injured tissue. Efficient injury repair in the lung is critical to reestablish gas exchange with the cardiovascular system, a process that is necessary to sustain life. Two key players in the gas exchange process in the distal lung are the type I alveolar epithelial cells and the capillary endothelial cells (ECs), which interface closely with each other to enable transfer of oxygen and carbon dioxide between them. During lung regeneration, distinct subpopulations of capillary ECs may possess cellular plasticity that enables them to act as endothelial progenitors to rebuild the gas exchange machinery. In addition, angiocrine signaling originating from ECs in the distal lung may shape the regeneration of other alveolar cell types. Despite the importance of ECs, however, the extent and function of their heterogeneity within the lung remains incompletely understood. This question is critical to our understanding of the maintenance and repair of functional gas exchange. I have profiled pulmonary EC heterogeneity at single-cell resolution using single-cell RNA sequencing in the adult mouse lung at homeostasis and after acute lung injury and have identified several unique EC populations. These include a subset of ECs that express high levels of signaling molecules and preferentially localize to regions of dense alveolar damage, as well as a population of highly proliferative ECs that arises upon acute lung injury. Each population likely contributes to revascularization of the alveolar space during regeneration. Determining the unique functional role of each population within the alveolus, its preferential response to injury, and how each type of EC interacts with alveolar epithelial cells will facilitate a better understanding of how the lung vasculature is rebuilt and gas exchange is reestablished as the lung regenerates. This mechanistic understanding can then be used to facilitate regenerative medicine approaches that target specific EC subtypes or signaling pathways in the lung. This project will expand my training to include key methods and concepts in lung regeneration and in bioinformatics analysis of single-cell genomic datasets. It will take place under the sponsorship of Dr. Edward Morrisey, a leader in the pulmonary biology field who has defined many key transcription factors and signaling pathways in the lung. This work will be conducted at the University of Pennsylvania, a world-class research institution with collaborative investigators, a rich intellectual environment, and extensive resources for the pursuit of biomedical research focusing on pulmonary biology. Together, the research and training plans proposed herein will facilitate a better understanding of pulmonary endothelial cell heterogeneity and its role in regeneration while preparing me for my future career as an independent investigator in the field of lung regeneration.

项目概要 肺在稳态时的细胞更新率较低，但含有兼性干细胞， 可以被激活以再生受伤的组织。肺部的有效损伤修复对于重建气体至关重要 与心血管系统的交换，这是维持生命所必需的过程。天然气领域的两个关键人物 远端肺的交换过程是I型肺泡上皮细胞和毛细血管内皮细胞（EC）， 它们彼此紧密结合，以实现氧气和二氧化碳在它们之间的转移。期间 在肺再生过程中，毛细血管内皮细胞的不同亚群可能具有细胞可塑性，使它们能够 作为内皮祖细胞重建气体交换机制。此外，血管分泌信号起源 来自远端肺内皮细胞的细胞可能会影响其他肺泡细胞类型的再生。尽管很重要 然而，EC 在肺内的异质性程度和功能仍不完全清楚。 这个问题对于我们理解功能性气体交换的维护和修复至关重要。 我使用单细胞 RNA 测序以单细胞分辨率分析了肺 EC 异质性 研究人员对处于稳态和急性肺损伤后的成年小鼠肺进行了研究，并确定了几种独特的 EC 人口。其中包括表达高水平信号分子的 EC 子集，并且优先 定位于密集的肺泡损伤区域，以及出现的高度增殖的 EC 群体 急性肺损伤。每个群体都可能有助于肺泡腔的血运重建 再生。确定肺泡内每个群体的独特功能作用，其优先 对损伤的反应，以及每种类型的 EC 如何与肺泡上皮细胞相互作用将有助于更好地 了解随着肺再生，肺血管系统如何重建以及气体交换如何重建。 这种机制上的理解可以用来促进针对目标的再生医学方法 肺部特定的 EC 亚型或信号通路。 该项目将扩大我的培训范围，包括肺再生和肺再生的关键方法和概念。 单细胞基因组数据集的生物信息学分析。它将在爱德华博士的赞助下进行 Morrisey，肺生物学领域的领导者，定义了许多关键的转录因子和信号传导 肺部的通路。这项工作将在世界一流的研究机构宾夕法尼亚大学进行 拥有协作研究人员、丰富的智力环境和广泛的资源的机构 专注于肺部生物学的生物医学研究。共同提出的研究和培训计划 本文将有助于更好地理解肺内皮细胞异质性及其在再生中的作用 同时为我未来作为肺再生领域的独立研究者的职业生涯做好准备。