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.

项目总结