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.

项目摘要 肺在体内稳态时具有较低的细胞周转率，但含有辅助干细胞 可以激活以再生受伤的组织。肺部有效损伤修复对于重新建立气体至关重要 与心血管系统交流，这是维持生命所必需的过程。气体中的两个主要参与者 远端肺的交换过程是I型肺泡上皮细胞和毛细管内皮细胞（ECS）， 它们彼此紧密接触，以使氧气和二氧化碳之间的转移。期间 肺部再生，毛细管EC的不同亚群可能具有细胞可塑性，使它们能够 充当内皮祖细胞，以重建气体交换机械。另外，血管分泌信号源 远端肺中的EC可以塑造其他肺泡细胞类型的再生。尽管很重要 然而，EC在肺部内的异质性的程度和功能尚不完全理解。 这个问题对于我们对功能气体交换的维护和维修的理解至关重要。 我使用单细胞RNA测序在单细胞分辨率下介绍了肺EC异质性 成年小鼠肺肺部和急性肺损伤后，已经确定了几个独特的EC 人群。这些包括一部分EC的子集，该EC表达高水平的信号分子并优先 位于严重肺泡损伤的区域，以及产生的高度增殖EC的种群 急性肺损伤。每个人群可能有助于在 再生。确定肺泡内每个人群的独特功能作用，并优先 对损伤的反应，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 了解如何重建肺脉管系统，并随着肺部再生而重新建立气体交换。 然后，这种机械理解可以用来促进针对的再生医学方法 肺中的特定EC亚型或信号通路。 该项目将扩大我的培训，以包括肺部再生中的关键方法和概念 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举行 莫里西（Morrisey）是肺部生物学领域的领导者，他定义了许多关键转录因子和信号传导 肺中的途径。这项工作将在宾夕法尼亚大学进行，这是一项世界一流的研究 与合作调查人员，丰富的智力环境和广泛的追求资源的机构机构 针对肺部生物学的生物医学研究。共同提出的研究和培训计划 这里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 在为我的未来职业做准备的同时，在肺部再生领域的独立研究者。