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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的气管软化是下呼吸道最常见的结构异常。估计发病率儿童的比例为 1,500 分之一到 2,500 分之一。气管软化症通常与先天性相关综合征性疾病和先天性气管软化症通常与软骨完整性受损有关代表症状严重、消退百分比较小、死亡率较高的患者。现在，手术干预是唯一的选择，这需要不成比例的高额医疗保健分配资源。缺乏对气管软骨发育及其病理生理学的认识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症。 BMP 信号传导已被证明是细胞生长所必需的关键生长因子然而，软骨形成和软骨发育，BMP 信号在气管软骨形成过程中是如何调节的发展尚未研究。 EvC 综合征 (OMIM 225500) 是一种常染色体隐性遗传病软骨发育不良。 EvC 患者中已有新生儿气道塌陷后死亡的记录综合症。我们使用 Evc2 突变小鼠的初步研究揭示了潜在的新机制调节前肠间质和气管间质中的 BMP 信号传导。我们已经证明了前肠和气管间质中精心策划的 BMP 信号对于气管软骨是必需的发育成正确的形状。我们的初步研究使我们假设： Hedgehog-BMP 轴位于前肠间质决定气管间质及其后续的 BMP 信号水平软骨形成；气管和食管分离后，细胞外储存的BMP配体发挥关键作用诱导气管间质中的 BMP 信号传导以促进随后的软骨形成；以及该行政当局 FK506 有潜力纠正 Evc2 突变小鼠的先天性气管软骨缺陷。这假设将通过以下三个目标进行研究：1）证明Hedgehog-BMP轴前肠间充质对于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储存的 BMP 配体在诱导软骨分化中的作用气管间质； 3) 证明 BMP 信号传导的药理学升高将挽救气管软骨发育缺陷。拟议工作的结果将揭示分子网络控制气管软骨的发育，这将直接建立气管软骨的知识库实用的治疗解决方案。