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

摘要 气管软化是下呼吸道最常见的结构异常。年的估计发病率 儿童的比例从1500人中有1人到2500人中有1人不等。气管软化常与先天性 与软骨完整性受损相关的综合征和先天性气管软化通常 代表症状严重、消退率较低、死亡率较高的患者。目前， 手术干预是唯一的选择，这需要高得不成比例的卫生保健分配 资源。对气管软骨发育和病理生理的认识不足 导致气管软骨完整性受损的机制阻止寻找替代干预措施 先天性气管软化症。BMP信号已被证明是一种关键的生长因子， 软骨发生和软骨发育，然而，BMP信号是如何在气管软骨中调节的 还没有对发展进行调查。上腔静脉综合征(OMIM 225500)是一种常染色体隐性遗传 软骨发育不良。EVC患者因呼吸道塌陷而死亡的新生儿已有记录 综合症。我们对Evc2突变小鼠的初步研究揭示了可能的新机制 调节前肠间充质和气管间充质中的BMP信号。我们已经证明了 前肠和气管间充质中协调良好的BMP信号对气管软骨是必要的 发展成正确的形状。我们的初步研究使我们假设：Hedgehog-BMP轴在 前肠间充质决定了BMP在气管间充质和随后的 软骨形成；在气管和食道分离后，细胞外储存的BMP配体起着关键作用 在诱导气管间充质中BMP信号以促进随后的软骨形成；以及给药 FK506具有纠正Evc2突变小鼠先天性气管软骨缺陷的潜力。这 假说将通过以下三个目的进行研究：1)证明Hedgehog-BMP轴 在前肠内，间充质对气管软骨的发育至关重要；2)评估 间充质合成和细胞外储存BMP配体诱导兔成软骨细胞分化 3)证明BMP信号的药理上调将挽救 气管软骨发育中的缺陷。拟议工作的结果将揭开分子 网络支配着气管软骨的发展，它将直接为 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.