Cellular and molecular control of human embryonic alveolar development: towards lung regeneration

在人类胚胎发育过程中，肺是最后完全形成并准备出生的器官之一。当婴儿早产时，正常的胚胎肺发育会中断，许多早产儿需要呼吸支持。这些儿童中的一些，特别是最早出生的儿童，会发展成一种名为支气管肺发育不良(BPD)的长期肺部疾病。然而，即使不经常发生BPD的早产儿，一生中肺功能也会下降。这些事实表明，胚胎肺发育的中断并不是在儿童成长过程中自然发生的。世界卫生组织估计，每年有1500万名婴儿早产，而且这个数字还在稳步上升。这项建议的目的是研究人类胚胎肺发育的正常机制，以确定改善早产儿肺健康的新策略。令人惊讶的是，人们对在人类胚胎中共同构建肺的细胞类型知之甚少，更不知道协调这一过程的细胞间通讯机制。该项目将不再使用肺发育的动物模型，而是将重点放在使用人类胚胎肺研究人类胚胎肺发育上。由于分子遗传学的进步和在实验室中将人体器官培养成微型器官或有机类化合物的新技术，这现在是可能的。我们将确定参与构建肺的不同细胞，并确定这些细胞用来相互通信的信号。这项研究将为人类正常的肺发育提供一个基线，使我们能够确定可以开发促进肺成熟的治疗方法的点。此外，在这个项目期间，我们将改进我们在实验室中培养人类微肺的技术。这些迷你肺将为我们提供一个系统来调查一些早产儿肺部疾病的遗传原因，如BPD。这些基因实验将有助于开发新的疾病标记物，帮助医生确定哪些早产儿有风险。此外，他们还将提供一个系统，在其中可以测试减少BPD和其他与早产相关的肺部问题的治疗方法。

During human embryonic development the lung is one of the last organs to become fully formed and ready for birth. When a baby is born prematurely normal embryonic lung development is interrupted and many premature infants require breathing support. Some of these children, particularly the most premature, develop a long-term lung condition called bronchopulmonary dysplasia (BPD). However, even premature infants who do not develop BPD frequently have decreased lung function throughout life. These facts illustrate that interruptions in embryonic lung development are not naturally caught-up during childhood growth. The Wold Health Organisation estimates that every year 15 million babies are born prematurely and that this figure is steadily rising. The aim of this proposal is to study the normal mechanisms of human embryonic lung development in order to identify new strategies to improve the lung health of premature infants.Surprisingly little is known about the cell types which work together to build a lung in the human embryo and even less is known about the cell-cell communication mechanisms that coordinate the process. Instead of working with animal models of lung development, this project will focus on studying human embryonic lung development using human embryonic lungs. This is now possible due to advances in molecular genetics and new techniques for growing human organs in the laboratory as mini-organs, or organoids. We will identify the different cells that are involved in building the lung and determine the signals that these cells use to communicate with each other. This study will provide a base-line for normal human lung development, allowing us to identify points for which therapies could be developed to promote lung maturation. In addition, during this project we will improve our techniques for growing human mini-lungs in the laboratory. These mini-lungs will provide a system for us to investigate the genetic causes of some premature lung conditions like BPD. These genetic experiments will assist with the development of new markers for the disease helping doctors to determine which premature babies are at risk. In addition, they will provide a system in which treatments to reduce the effects of BPD, and other lung problems associated with prematurity, can be tested.