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:
  • 金额:
    $ 39万
  • 依托单位:
  • 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

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.
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的BMP信号水平以及随后的 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。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Yuji MISHINA其他文献

Yuji MISHINA的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Yuji MISHINA', 18)}}的其他基金

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:
    10599970
  • 财政年份:
    2022
  • 资助金额:
    $ 39万
  • 项目类别:
A new model for spatio-temporal coupling of bone formation and bone resorption governed by osteoclasts
破骨细胞控制的骨形成和骨吸收时空耦合的新模型
  • 批准号:
    10905262
  • 财政年份:
    2020
  • 资助金额:
    $ 39万
  • 项目类别:
A new model for spatio-temporal coupling of bone formation and bone resorption governed by osteoclasts
破骨细胞控制的骨形成和骨吸收时空耦合的新模型
  • 批准号:
    10082528
  • 财政年份:
    2020
  • 资助金额:
    $ 39万
  • 项目类别:
A new model for spatio-temporal coupling of bone formation and bone resorption governed by osteoclasts
破骨细胞控制的骨形成和骨吸收时空耦合的新模型
  • 批准号:
    10249332
  • 财政年份:
    2020
  • 资助金额:
    $ 39万
  • 项目类别:
Molecular pathogenesis of craniosynostosis caused by enhanced BMP signaling
BMP信号增强导致颅缝早闭的分子发病机制
  • 批准号:
    8230522
  • 财政年份:
    2010
  • 资助金额:
    $ 39万
  • 项目类别:
Molecular pathogenesis of craniosynostosis caused by enhanced BMP signaling
BMP信号增强导致颅缝早闭的分子发病机制
  • 批准号:
    9262071
  • 财政年份:
    2010
  • 资助金额:
    $ 39万
  • 项目类别:
Molecular pathogenesis of craniosynostosis caused by enhanced BMP signaling
BMP信号增强导致颅缝早闭的分子发病机制
  • 批准号:
    8064718
  • 财政年份:
    2010
  • 资助金额:
    $ 39万
  • 项目类别:
Molecular pathogenesis of craniosynostosis caused by enhanced BMP signaling
BMP信号增强引起的颅缝早闭的分子发病机制
  • 批准号:
    9902971
  • 财政年份:
    2010
  • 资助金额:
    $ 39万
  • 项目类别:
Molecular pathogenesis of craniosynostosis caused by enhanced BMP signaling
BMP信号增强导致颅缝早闭的分子发病机制
  • 批准号:
    8415957
  • 财政年份:
    2010
  • 资助金额:
    $ 39万
  • 项目类别:
Molecular pathogenesis of craniosynostosis caused by enhanced BMP signaling
BMP信号增强导致颅缝早闭的分子发病机制
  • 批准号:
    8510106
  • 财政年份:
    2010
  • 资助金额:
    $ 39万
  • 项目类别:

相似海外基金

Hormone therapy, age of menopause, previous parity, and APOE genotype affect cognition in aging humans.
激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
  • 批准号:
    495182
  • 财政年份:
    2023
  • 资助金额:
    $ 39万
  • 项目类别:
Investigating how alternative splicing processes affect cartilage biology from development to old age
研究选择性剪接过程如何影响从发育到老年的软骨生物学
  • 批准号:
    2601817
  • 财政年份:
    2021
  • 资助金额:
    $ 39万
  • 项目类别:
    Studentship
RAPID: Coronavirus Risk Communication: How Age and Communication Format Affect Risk Perception and Behaviors
RAPID:冠状病毒风险沟通:年龄和沟通方式如何影响风险认知和行为
  • 批准号:
    2029039
  • 财政年份:
    2020
  • 资助金额:
    $ 39万
  • 项目类别:
    Standard Grant
Neighborhood and Parent Variables Affect Low-Income Preschool Age Child Physical Activity
社区和家长变量影响低收入学龄前儿童的身体活动
  • 批准号:
    9888417
  • 财政年份:
    2019
  • 资助金额:
    $ 39万
  • 项目类别:
The affect of Age related hearing loss for cognitive function
年龄相关性听力损失对认知功能的影响
  • 批准号:
    17K11318
  • 财政年份:
    2017
  • 资助金额:
    $ 39万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    9320090
  • 财政年份:
    2017
  • 资助金额:
    $ 39万
  • 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    10166936
  • 财政年份:
    2017
  • 资助金额:
    $ 39万
  • 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    9761593
  • 财政年份:
    2017
  • 资助金额:
    $ 39万
  • 项目类别:
How age dependent molecular changes in T follicular helper cells affect their function
滤泡辅助 T 细胞的年龄依赖性分子变化如何影响其功能
  • 批准号:
    BB/M50306X/1
  • 财政年份:
    2014
  • 资助金额:
    $ 39万
  • 项目类别:
    Training Grant
Inflamm-aging: What do we know about the effect of inflammation on HIV treatment and disease as we age, and how does this affect our search for a Cure?
炎症衰老:随着年龄的增长,我们对炎症对艾滋病毒治疗和疾病的影响了解多少?这对我们寻找治愈方法有何影响?
  • 批准号:
    288272
  • 财政年份:
    2013
  • 资助金额:
    $ 39万
  • 项目类别:
    Miscellaneous Programs
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了