Mechanical regulation of branching morphogenesis

项目总结 脊椎动物的肺通过一个被称为分支形态发生的过程来发育，其中亚群 重复地指示上皮细胞形成裂隙或芽，从而产生一棵具有 有足够的表面积进行气体交换，以支持出生后的呼吸。反常的机械环境 胸腔内可扰乱分支并导致胎儿肺发育不全，这是导致 新生儿呼吸功能不全。目前尚不清楚机械应力如何控制或破坏分支。 程序。在这里，我们描述了将组织工程学方法与完整的 胚胎肺定义机械应激如何转化为驱动基因表达变化 分枝形态发生。工程肺组织和计算模型将被用来预测这种作用 分支部位起始处的机械应力。在具体目标1中，我们将确定是否以及如何 机械应力调节工程化胚胎小鼠肺组织的分枝形态发生 完整的雏鸡和小鼠胚胎肺。在特定目标2中，我们将定义机械诱导基因 驱动肺分支的表达变化。据我们所知，这项工作将是第一次 培养或体内分枝形态发生过程中机械响应基因的综合分析。 我们期望揭示的基因表达模式将为探索医学的新途径开辟新的途径 治疗机械性疾病，如胎儿肺发育不全。

PROJECT SUMMARY 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.