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.

项目概要 肺在体内平衡中的一个关键功能是通过一个称为“呼吸”的过程将氧气输送到血液中。 气体交换。当肺功能正常时，I型肺泡上皮细胞和毛细血管内皮细胞 远端肺血管内壁细胞（EC）形成紧密的界面来交换氧气和二氧化碳 他们之间。然而，当肺部因慢性疾病、癌症或流感等感染而受损时 或 COVID-19，这一过程可能会受到阻碍甚至阻止。肺损伤后，祖细胞可以再生 气体交换所需的细胞类型，但细胞间通讯对于形成功能性细胞也至关重要 恢复向血液输送氧气的结构。改进再生疗法的开发 因此，肺不仅需要详细了解存在的特定细胞类型，还需要了解如何 它们通过交流来驱动细胞自组织和形态发生。我们已经证明，毛细管 ECs 远端肺是异质的；一个群体充当 EC 祖细胞并在急性损伤后增殖 (CAP2s)，而第二个群体在受伤后不会显着增殖，并且拥有更大、更多的 复杂的形态和信号分子（CAP1s）的高表达。这些 EC 亚型明显有助于 与再生不同，但不同的 EC 命运是如何建立和维持的，其机制 促进 CAP2 的优先增殖，而 CAP1 的信号传导功能仍不清楚。此外， 肺泡微环境中影响形态发生和重建肺泡微环境所需的 EC 信号机制 气体交换界面仍然不完全清楚。拟议的研究将进一步发展我的技能 转录组和表观基因组分析来解决这些问题，并将这些技能与我的 之前在小鼠遗传学、信号传导和细胞行为方面的培训，为以后的研究奠定了坚实的基础 建立独立的研究生涯。我的研究项目将重点关注 EC 信号传导和行为的作用 急性损伤后肺功能性肺泡结构的再生。我的主要导师是爱德华博士 莫里西（Morrisey）是一位国际知名的肺再生研究科学家，他定义了许多关键的 肺部细胞命运和信号传导机制的调节者。我还组建了一个咨询委员会 血管生物学、小鼠和人类类器官培养、表观遗传学和生物信息学专家将提供协助 我在这些领域接受了额外的培训。拟议的工作将在宾夕法尼亚大学进行， 在那里我将受益于丰富的智力环境、广泛的资源、协作的科学界 在肺和血管生物学方面，以及该机构的全力支持。我提出的研究和 职业发展计划将有助于更好地了解 EC 信号在肺再生中的作用 并帮助我建立作为肺血管生物学独立研究者的职业生涯。