Endothelial cell signaling in regeneration of the lung

肺再生中的内皮细胞信号传导

• 批准号: 10506642
• 负责人: Terren Kathryn Niethamer
• 金额: $ 16.17万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10506642
• 关键词: ATAC-seq; Acute; Acute Lung Injury; Address; Advisory Committees; Alveolar; Alveolar Cell; Alveolus; Architecture; Area; Bioinformatics; Biology; Blood; Blood Vessels; Blood capillaries; COVID-19; Candidate Disease Gene; Capillary Endothelial Cell; Carbon Dioxide; Cardiovascular system; Cell Communication; Cell Differentiation process; Cell Line; Cell Proliferation; Cells; Cellular biology; Chronic Disease; Communication; Communities; Complex; Data; Development; Development Plans; Distal; Elastases; Endothelial Cells; Endothelium; Environment; Epigenetic Process; Epithelial; Epithelial Cells; Foundations; Functional Regeneration; Gases; Genetic Transcription; Heterogeneity; Homeostasis; Human; Image; Immune; Individual; Infection; Influenza; Injury; Institution; International; KDR gene; Knock-out; Knowledge; Ligands; Lung; Lung diseases; Malignant Neoplasms; Mammals; Mentors; Mesenchymal; Morphogenesis; Morphology; Mus; Natural regeneration; Organ; Organoids; Oxygen; Patients; Pennsylvania; Phase; Population; Positioning Attribute; Process; Proliferating; Pulmonary alveolar structure; Pulmonary function tests; Receptor Signaling; Regenerative capacity; Research; Research Personnel; Resources; Role; Scientist; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Structure; Structure of parenchyma of lung; Time; Tissues; Training; Universities; Vascular regeneration; Viral; Work; alveolar epithelium; career; career development; cell behavior; cell regeneration; cell type; endothelial stem cell; epigenomics; genetic approach; improved; in vivo; influenza infection; injured; injury and repair; insight; lung injury; lung regeneration; mouse genetics; novel; post-doctoral training; prevent; progenitor; programs; pulmonary function; pulmonary vascular cells; receptor; reconstruction; regenerative; regenerative therapy; repaired; research and development; response; self organization; severe injury; single-cell RNA sequencing; skills; stem cells; transcriptome sequencing; transcriptomics

Project Summary A critical function of the lung at homeostasis is delivery of oxygen to the blood through a process called gas exchange. When the lung is functioning normally, type I alveolar epithelial cells and capillary endothelial cells (ECs) lining blood vessels in the distal lung form a tight interface to exchange oxygen and carbon dioxide between them. However, when the lung is damaged by chronic disease, cancer, or infections such as influenza or COVID-19, this process can be hindered or even prevented. After lung injury, progenitor cells can regenerate the cell types required for gas exchange, but cell-cell communication is also essential to form a functional structure that restores delivery of oxygen to the blood. Development of improved regenerative therapies in the lung will therefore require a detailed knowledge of not only the specific cell types that are present, but also how they communicate to drive cell self-organization and morphogenesis. We have shown that capillary ECs in the distal lung are heterogeneous; one population acts as an EC progenitor and proliferates after acute injury (CAP2s), while a second population does not proliferate significantly after injury and possesses a larger, more complex morphology and high expression of signaling molecules (CAP1s). These EC subtypes clearly contribute differently to regeneration, but how distinct EC fates are established and maintained, the mechanisms that promote the preferential proliferation of CAP2s, and the signaling function of CAP1s remain unknown. In addition, the EC signaling mechanisms within the alveolar niche that are required to effect morphogenesis and rebuild the gas exchange interface remain incompletely understood. The proposed research will further develop my skills in transcriptomic and epigenomic analysis to address these questions and will integrate these skills with my previous training in mouse genetics, signaling, and cell behavior to establish a strong foundation on which to build an independent research career. My research program will focus on the role of EC signaling and behavior in regeneration of functional alveolar structures in the lung after acute injury. My primary mentor is Dr. Edward Morrisey, an internationally renowned scientist in the study of lung regeneration who has defined many key regulators of cell fate and signaling mechanisms in the lung. I have also assembled an advisory committee of experts in vascular biology, mouse and human organoid culture, epigenetics, and bioinformatics who will assist me with additional training in these areas. The proposed work will be conducted at the University of Pennsylvania, where I will benefit from the rich intellectual environment, extensive resources, collaborative scientific community in pulmonary and vascular biology, and the full support of the institution. Together, my proposed research and career development plans will facilitate a better understanding of the role of EC signaling in lung regeneration and aid in establishing my career as an independent investigator in pulmonary vascular biology.

项目总结