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

BMP 信号在气管软骨模式化中的时间调节和预防气管软化的药理学方法

• 批准号: 10417330
• 负责人: Yuji MISHINA
• 金额: $ 39万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10417330
• 关键词: Acute; Affect; Age; Airway Disease; Animal Model; Attenuated; Bone Morphogenetic Proteins; Breathing; Cartilage; Child; Chondrogenesis; Chronic Obstructive Airway Disease; Cytoskeleton; Data; Death Rate; Defect; Development; Disease; Dose; Ensure; Erinaceidae; Esophagus; FBN1; FK506; Failure to Thrive; Foundations; Functional disorder; Genes; Genetic; Goals; Growth Factor; Healthcare; Impairment; Incidence; Individual; Infant; Intervention; Knowledge; Lead; Life; Ligands; Mesenchymal; Mesenchyme; Modeling; Molecular; Mutant Strains Mice; Online Mendelian Inheritance In Man; Operative Surgical Procedures; Outcome; Pathologic; Patients; Pattern; Perinatal mortality demographics; Pharmacology; Phenotype; Physical condensation; Play; Primitive foregut structure; Proteins; Regulation; Resources; Respiratory Failure; Role; Scheme; Shapes; Signaling Protein; Structural defect; Sudden Death; Symptoms; Syndrome; Therapeutic; Therapeutic Intervention; Tissues; Toxic effect; Trachea; Tracheal Epithelium; Tracheostomy procedure; Work; base; cartilage development; chondrodysplasia; extracellular; gain of function; insight; knowledge base; loss of function; mortality; neonatal death; novel; pediatric patients; prevent; restoration; smoothened signaling pathway; success; tool

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.

抽象的 气管气囊是下气道中最常见的结构异常。估计发病率 儿童的范围从1,500分之1到2,500分之一。气管菌经常与先天性有关 与软骨完整性受损相关的综合征疾病和先天性气管疾病 代表患有严重症状，消退百分比和更高死亡率的人。现在， 手术干预是唯一的选择，它需要不成比例的医疗保健分配 资源。缺乏关于气管软骨发育和病理生理学的知识 机制导致气管软骨完整性受损，以阻止寻找其他干预措施 先天性气管毛。 BMP信号已被证明是必要的关键生长因子 然而，软骨发生和软骨发育，在气管软骨期间如何调节BMP信号传导 开发尚未进行调查。 EVC综合征（OMIM 225500）是常染色体隐性 软骨增生。 EVC患者已记录了气道崩溃后的新生儿死亡 综合征。我们使用EVC2突变小鼠的初步研究发现了有关该领域的潜在新机制 在前肢间充质和气管间充质中调节的BMP信号。我们已经证明了 对于气管软骨，必须进行良好的预言和气管间充质的BMP信号传导是必要的 发展成正确的形状。我们的初步研究导致我们假设：刺猬-BMP轴 前肠间充质决定气管间充质和随后的BMP信号传导水平 软骨发生；气管和食道分离后，细胞外存储的BMP配体起着关键作用 在气管间充质中诱导BMP信号传导以随后的软骨形成；和管理 FK506有可能纠正EVC2突变小鼠中先天性有缺陷的气管软骨。这 假设将通过以下三个目标进行研究：1）证明刺猬-BMP轴 在前肢间充质中，对气管软骨的发育至关重要。 2）评估角色 间充质合成和细胞外存储的BMP配体在诱导软骨分化 气管间充质； 3）证明BMP信号的药理升高将拯救 气管软骨发育中的缺陷。提议的工作的结果将发现分子 网络管理气管软骨开发，该开发将直接建立知识库 实用的治疗解决方案。