Endothelial cell signaling in regeneration of the lung

项目摘要 肺在体内平衡时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 肺远端血管的内皮细胞（EC）形成紧密的界面，以交换氧气和二氧化碳 他们之间然而，当肺部受到慢性疾病、癌症或流感等感染的损害时， 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，但细胞间通讯也是形成功能性 恢复向血液输送氧气的结构。发展改进的再生疗法， 因此，肺不仅需要详细了解存在的特定细胞类型，而且还需要了解它们是如何存在的。 它们相互交流以驱动细胞的自我组织和形态发生。我们已经证明， 远端肺是异质的;一个群体作为EC祖细胞，在急性损伤后增殖 （CAP 2），而第二个群体在损伤后不显著增殖，并具有更大，更大的细胞增殖能力。 复杂的形态和高表达的信号分子（CAP 1）。这些EC亚型显然有助于 不同的再生，但如何建立和维持不同的EC命运， 促进CAP 2的优先增殖，CAP 1的信号传导功能尚不清楚。此外，本发明还提供了一种方法， 肺泡生态位内的EC信号传导机制是影响形态发生和重建细胞所必需的。 气体交换界面仍不完全清楚。拟议的研究将进一步发展我的技能， 转录组学和表观基因组学分析来解决这些问题，并将这些技能与我的 先前在小鼠遗传学，信号传导和细胞行为方面的培训，以建立坚实的基础， 建立独立的研究生涯。我的研究计划将集中在EC信号和行为的作用 在急性损伤后肺中功能性肺泡结构的再生中。我的主要导师是爱德华博士 Morrisey是一位研究肺再生的国际知名科学家，他定义了许多关键的 肺中细胞命运和信号传导机制的调节剂。我还召集了一个咨询委员会， 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方面的专家， 在这些领域进行额外的培训。拟议的工作将在宾夕法尼亚大学进行， 在那里，我将受益于丰富的知识环境，广泛的资源，协作的科学界， 在肺和血管生物学方面，以及机构的全力支持。我的研究计划和 职业发展计划将有助于更好地理解EC信号在肺再生中的作用 并帮助我建立了作为肺血管生物学独立研究者的职业生涯。

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.