Mechanical Control of Smooth Muscle Differentiation During Mouse Lung Branching

小鼠肺分支过程中平滑肌分化的机械控制

• 批准号: 10434474
• 负责人: Jacob Michael Jaslove
• 金额: $ 1.58万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434474
• 关键词: Mechanical; Control; Smooth; Muscle; Differentiation

Project Summary Diseases arising from lung developmental disorders are widespread and often deadly. Our abilities to develop therapies for these disorders or to engineer artificial lungs in the laboratory are limited by our incomplete understanding of how the complex and stereotyped architecture of the lung develops. The smooth muscle that surrounds the airways (airway smooth muscle, ASM) has recently been shown to play a role in the bifurcation of epithelial buds, an important step in the development of the branched structure of the lung. To help drive bifurcation, ASM must differentiate from the mesenchyme surrounding epithelial bud tips in a precise and asymmetric pattern, but the mechanisms controlling this spatial pattern of differentiation are poorly understood. Signaling molecules, like sonic hedgehog and bone morphogenic protein-4, and mechanical cues, like the pressure inside the developing airway, are known to increase smooth muscle differentiation. I hypothesize that the transpulmonary pressure causes a distribution of mechanical stress in the mesenchyme that specifies the spatial pattern of smooth muscle differentiation around bud tips. Confirming this hypothesis would support a model in which mesenchymal cells around bud tips are primed to be potential ASM precursors by signaling molecules, but the precise pattern of mechanical stress determines which potential precursors differentiate into ASM. To test the hypothesis, I will determine whether stretch can induce airway mesenchymal cells to adopt an ASM phenotype in culture (Aim 1). I will then analyze RNA sequencing data of lungs cultured under high and low pressure to understand potential molecular mechanisms by which transpulmonary pressure is transduced into a morphogenetic signal (Aim 2). Finally, I will use computational models of lung volumetric reconstructions to determine whether bud epithelial geometry and transpulmonary pressure are sufficient to cause stress distributions in the mesenchyme that predict the pattern of ASM differentiation at bud tips (Aim 3). Successfully completing these aims will deepen our understanding of how ASM differentiates and how transpulmonary pressure affects lung development. This knowledge could inform future research into therapies that modulate ASM differentiation to treat congenital lung diseases and future efforts to direct the differentiation of smooth muscle in tissue-engineered lungs.

项目摘要 肺发育障碍引起的疾病广泛，而且经常致命。我们发展的能力 这些疾病的疗法或实验室中的人造肺部的疗法受到我们不完整的限制 了解肺的复杂和刻板印象的建筑如何发展。平滑肌 周围环绕气道（气道平滑肌，ASM）最近已显示出在分叉中发挥作用 上皮芽，这是肺部分支结构发展的重要步骤。帮助开车 分叉，ASM必须精确地与周围的上皮芽尖端区分开 不对称模式，但是控制这种分化空间模式的机制知之甚少。 信号分子（如声音刺猬和骨形态发生蛋白4）以及机械提示，例如 已知发育中的气道内部的压力会增加平滑肌的差异。我假设这一点 肺压力导致在间充质中的机械应力分布，以指定 芽尖附近平滑肌分化的空间模式。确认这一假设将支持 模型中，芽尖周围的间充质细胞通过信号传导启动为潜在的ASM前体 分子，但机械应力的精确模式决定了哪些潜在前体分化为 ASM。为了检验假设，我将确定是否伸展可以诱导气道间充质细胞采用 文化中的ASM表型（AIM 1）。然后，我将分析在高中培养的肺的RNA测序数据 以及低压，以理解转肺压力的潜在分子机制 转导为形态发生信号（AIM 2）。最后，我将使用肺体积的计算模型 重建以确定芽上皮的几何形状和转肺压力是否足以 在间充质中引起应力分布，以预测芽尖端的ASM分化模式（AIM 3）。 成功完成这些目标将加深我们对ASM如何区分以及如何区分的理解 肺压力影响肺发育。这些知识可以为未来的疗法研究提供信息 这种调节ASM差异化以治疗先天性肺部疾病和未来指导差异化的努力 组织工程肺中的平滑肌。