Reverse Engineering the Pulmonary Microvasculature

项目摘要/摘要 全球肺部疾病的负担是巨大的，急性肺部病变影响到100-500万人。 每年和慢性阻塞性肺病(COPD)是全球第四大死亡原因。这个 终末期疾病的最佳治疗方法是肺移植，其10年存活率不到30%。我们的 对肺细胞系统生物学、病理紊乱和组织内稳态的基本了解 确实是有限的。为了更好地治疗肺部疾病，有必要更好地了解组织生物学，并 需要根据基本原理和再生工程设计新的治疗方法。这 该项目旨在阐明肺泡微血管调节和动态平衡的基本途径， 然后将这些机制应用于再生工程。该提案分为三个具体部分 目标。在第一个目标中，将使用远端肺的单细胞RNA测序(ScRNAseq)来阐明潜在的 发育和成熟肺泡中微血管特异性生长因子的信号转导。在第二个目标中， 基于天然组织蛋白的表达和协同作用，可能的信号机制清单将进一步完善。 微血管定位。最后，在第三个目标中，将确定一组有限的增长因素 随着时间的推移被传递到体外器官模型，以评估它们对微血管发育和 功能。该项目的动机是最重要的假设，即理解增长因素信号 在组织水平上不仅有助于了解肺部的发育和病理，而且还将 强烈告知如何对再生医学的肺血管组织进行反向工程。 好了！

PROJECT SUMMARY/ABSTRACT The global burden of pulmonary disease is immense, with acute lung pathology affecting 1-5 million people annually and chronic obstructive pulmonary disease (COPD) the 4th leading cause of death worldwide. The best treatment for end-stage disease, lung transplantation, has a 10-year survival rate of less than 30%. Our fundamental understanding of lung cell systems biology, pathological derangements, and tissue homeostasis is truly limited. To better treat pulmonary disease, there is a need to better understand tissue biology, and a need to design new therapeutic approaches based on basic principles and regenerative engineering. This project aims to elucidate basic pathways governing microvascular regulation and homeostasis in the alveolus, and then apply those mechanisms for regenerative engineering. The proposal is divided into three specific aims. In the first aim, single-cell RNA sequencing (scRNAseq) of distal lung will be used to elucidate potential microvascular-specific growth factor signaling in the developing and mature alveolus. In the second aim, a putative list of signaling mechanisms will be further refined based on native tissue protein expression and co- localization with microvasculature. Finally, in the third aim, a limited set of identified growth factors will be delivered over time to an in vitro organotypic model to assess their effect on microvascular development and function. The project is motivated by the overarching hypothesis that understanding growth factoring signaling at the tissue level will not only aid in the understanding of pulmonary development and pathology, but will strongly inform how to “reverse-engineer” pulmonary vascular tissues for regenerative medicine. !