Temporal regulation of BMP signaling in patterning the tracheal cartilage and pharmacological approaches to prevent tracheomalacia

摘要 气管软化症是下呼吸道最常见的结构异常。估计发病率 儿童的比例从1/1 500到1/2 500不等。气管软化症通常与先天性 与软骨完整性受损相关的综合征疾病和先天性气管软化症通常 代表症状严重、消退率低、死亡率高的患者。目前， 手术干预是唯一的选择，这需要不成比例的高卫生保健分配 资源对气管软骨发育和病理生理学的认识不足， 导致气管软骨完整性受损的机制阻碍了寻找替代干预措施， 先天性气管软化BMP信号已被证明是一种关键的生长因子， 然而，在气管软骨形成和软骨发育过程中，BMP信号是如何调节的， 发展尚未调查。EvC综合征（OMIM 225500）是一种常染色体隐性遗传病， 软骨发育不良在EvC患者中，有记录显示新生儿死于气道塌陷 综合征我们使用Evc 2突变小鼠的初步研究揭示了在细胞凋亡中潜在的新机制。 调节前肠间充质和气管间充质中的BMP信号传导。我们已经证明 前肠和气管间充质中协调良好的BMP信号传导对于气管软骨是必要的， 形成正确的形状。我们的初步研究使我们假设：Hedgehog-BMP轴在 前肠间充质决定气管间充质中BMP信号传导水平， 软骨形成;气管和食管分离后，细胞外储存的BMP配体起关键作用 在气管间充质中诱导BMP信号传导用于随后软骨形成;以及施用 FK 506具有纠正Evc 2突变小鼠先天性气管软骨缺陷的潜力。这 假设将通过以下三个目的进行研究：1）为了证明Hedgehog-BMP轴 在前肠间充质内的细胞对气管软骨发育至关重要; 2）评估 间充质合成和细胞外储存的BMP配体在诱导软骨形成分化中的作用 3）为了证明BMP信号传导的药理学升高将拯救气管间充质; 气管软骨发育缺陷。这项工作的结果将揭示 神经网络控制着气管软骨的发育，这将直接为 实用的治疗方案。

ABSTRACT Tracheomalacia is the most common structural abnormality in the lower airway. The estimated incidence in children ranges from 1 in 1,500 to 1 in 2,500. Tracheomalacia is very often associated with congenital syndromic disorders and congenital tracheomalacia associated with impaired cartilage integrity often represents the ones with severe symptoms, less regression percentage and higher mortality rate. Currently, surgical intervention is the only option, which requires disproportionately high allocation of health care resources. The lack of knowledge on the tracheal cartilage development and the pathophysiological mechanisms lead to impaired tracheal cartilage integrity prevent searching for alternative interventions for congenital tracheomalacia. BMP signaling has been demonstrated as a critical growth factor necessary for chondrogenesis and cartilage development, however, how BMP signaling is regulated during tracheal cartilage development has not been investigated. EvC syndrome (OMIM 225500) is an autosomal recessive chondrodysplasia. Neonatal death subsequent to airway collapse has been documented in patients with EvC syndrome. Our preliminary studies using Evc2 mutant mice uncover the potential novel mechanisms on the regulated BMP signaling both in foregut mesenchyme and in tracheal mesenchyme. We have demonstrated that well-orchestrated BMP signaling in foregut and tracheal mesenchyme is necessary for tracheal cartilage developing into correct shape. Our preliminary studies lead us hypothesize that: Hedgehog-BMP axis at foregut mesenchyme determines the BMP signaling levels in tracheal mesenchyme and the subsequent chondrogenesis; after trachea and esophagus separation, extracellularly stored BMP ligands play a critical role in inducing BMP signaling in tracheal mesenchyme for subsequent chondrogenesis; and that administration of FK506 has the potential to correct the congenital defective tracheal cartilage in Evc2 mutant mice. This hypothesis will be investigated by the following three aims: 1) To demonstrate that the Hedgehog-BMP axis within the foregut mesenchyme is critical for tracheal cartilage development; 2) To evaluate roles of mesenchymally synthesized and extracellularly stored BMP ligands in inducing chondrogenic differentiation in tracheal mesenchyme; 3) To demonstrate that pharmacological elevation of BMP signaling will rescue the defects in tracheal cartilage development. The outcome of the proposed work will uncover the molecular networks govern the tracheal cartilage development, which will directly set up the knowledge base for the practical therapeutic solutions.