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

项目摘要 肺在动态平衡时细胞周转率低，但含有兼性干细胞 可以被激活以再生受伤的组织。有效的肺损伤修复是重建气体的关键 与心血管系统的交换，这是维持生命所必需的过程。天然气行业的两个关键人物 肺远端的交换过程是I型肺泡上皮细胞和毛细血管内皮细胞。 它们彼此紧密连接，以实现它们之间的氧气和二氧化碳的转移。在.期间 肺再生，不同的毛细血管内皮细胞亚群可能具有细胞可塑性，使它们能够 充当内皮祖细胞，重建气体交换机制。此外，血管分泌信号起源于 来自远端肺内皮细胞可能影响其他类型的肺泡细胞的再生。尽管重要的是 然而，ECS在肺内的异质性的程度和功能仍不完全清楚。 这个问题对我们理解功能性换气器的维护和维修至关重要。 我已经使用单细胞RNA测序在单细胞分辨率下分析了肺内皮细胞的异质性 成年小鼠肺处于动态平衡和急性肺损伤后并已鉴定出几种独特的EC 人口。这些细胞包括表达高水平信号分子的EC的子集，并且优先 定位于致密的肺泡损伤区域以及高增殖的内皮细胞 急性肺损伤。每个种群都可能对肺泡腔的血运重建做出贡献。 再生。确定每个种群在肺泡内的独特功能作用，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促进更好的 了解肺血管是如何重建的，气体交换是如何随着肺的再生而重建的。 这种机械论的理解然后可以用来促进再生医学的目标 肺中特定的EC亚型或信号通路。 这个项目将扩大我的培训范围，包括肺再生和 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是肺部生物学领域的领导者，他定义了许多关键的转录因子和信号转导 肺中的通路。这项工作将在宾夕法尼亚大学进行世界级的研究 具有协作调查人员的机构、丰富的知识环境和广泛的追查资源 专注于肺部生物学的生物医学研究。总的来说，研究和培训计划建议 这将有助于更好地了解肺内皮细胞的异质性及其在再生中的作用 同时为我未来的职业生涯做好准备，成为肺再生领域的一名独立研究员。

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.