Mechanical regulation of branching morphogenesis

描述(申请人提供)：脊椎动物的肺通过一个称为分支形态发生的过程发育，在这个过程中，重复地指示上皮细胞亚群形成裂隙或芽，从而产生具有足够表面积的空间填充树，以便出生后进行气体交换以支持呼吸。胸腔内异常的机械环境会扰乱分支，导致胎儿肺发育不良，这是新生儿呼吸功能不全的主要原因。目前尚不清楚机械压力是如何控制或破坏分支程序的。在这里，我们描述了将组织工程方法与完整胚胎肺的研究相结合的实验，以确定机械应力如何转化为驱动分支形态发生的基因表达变化。工程化肺组织和计算模型将被用来预测机械应力在分支部位起始中的作用。在特定的目标1中，我们将确定机械应力是否以及如何调节工程化胚胎小鼠肺组织以及完整的鸡和小鼠胚胎肺的分支形态发生。在特定的目标2中，我们将定义驱动肺分支的机械诱导的基因表达变化。据我们所知，这项工作将是第一次全面分析在培养或体内分枝形态发生中的机械响应基因。我们预计，揭示的基因表达模式将为探索机械诱导疾病(如胎儿肺发育不全)的医学治疗开辟新的途径。 与公共卫生相关：器官发育需要精致的控制过程，以确保适当的模式和功能形式的产生。越来越多的证据表明，机械应力参与了肺和其他树状器官的分支模式的发展，而异常的机械应力可导致人类胚胎肺部疾病。我们在这里提出了一种综合的方法来精确地定义机械应力是如何转化为驱动胚胎肺组织分支形态发生的基因表达变化的，这将使未来的研究能够治疗人类胚胎肺部疾病。

DESCRIPTION (provided by applicant): The vertebrate lung develops via a process known as branching morphogenesis, wherein subgroups of epithelial cells are instructed reiteratively to form clefts or buds and thereby generate a space-filling tree with a sufficient surface area for gas exchange to support breathing after birth. An aberrant mechanical environment within the thoracic cavity can disrupt branching and cause fetal pulmonary hypoplasia, a major cause of respiratory insufficiency of the newborn. It is unclear how mechanical stresses control or disrupt the branching program. Here, we describe experiments combining tissue engineering approaches with investigations of intact embryonic lungs to define how mechanical stresses are transduced into gene expression changes that drive branching morphogenesis. Engineered lung tissues and computational models will be used to predict the role of mechanical stresses in branch site initiation. In Specific Aim 1, we will determine whether and how mechanical stresses regulate branching morphogenesis of engineered embryonic mouse lung tissues and intact chick and mouse embryonic lungs. In Specific Aim 2, we will define the mechanically induced gene expression changes that drive lung branching. To our knowledge, this work will represent the first comprehensive analysis of mechanically responsive genes in branching morphogenesis in culture or in vivo. We expect that the gene expression patterns revealed will uncover new avenues to explore for medical treatment of mechanically-induced diseases such as fetal pulmonary hypoplasia. PUBLIC HEALTH RELEVANCE: Organ development requires exquisite control processes to ensure proper patterning and generation of functional forms. Increasing evidence suggests that mechanical stresses are involved in the development of the branching patterns of the lung and other tree-like organs, and that aberrant mechanical stresses can cause human fetal pulmonary diseases. We present here an integrated approach to define precisely how mechanical stresses are converted into gene expression changes that drive branching morphogenesis of embryonic lung tissues, which will enable future studies to treat human fetal pulmonary disease.