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

基本信息

  • 批准号:
    9902971
  • 负责人:
  • 金额:
    $ 21.2万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-06-07 至 2021-04-30
  • 项目状态:
    已结题

项目摘要

ABSTRACT Craniosynostosis is a debilitating condition characterized by premature cranial suture fusion resulting in abnormal skull shape. The estimated prevalence of craniosynostosis is 1:2,500 live births making it one of the most prevalent congenital malformations affecting the skeletal system. The only treatment is extensive, and often multiple, reconstructive surgeries. The long-term goal of the parent R01 is to define the molecular mechanism by which gain-of-function mutations in BMP signaling components lead to craniosynostosis in the rodent models. We have established a conditional mouse model, which shows enhanced neural crest-specific BMP signaling via BMP type 1 receptor BMPR1A in the skull and sutures. This model is unique and important due to: 1) upregulation of p53-induced apoptosis is observed, and 2) ectopic cartilage is formed at the site of fusion prior to premature fusion, suggesting that craniosynostosis is not a bone disease but stem cell disease. Our recent data strongly suggest that augmented BMP-Smad signaling activities influences cell fate specification of multi-potent neural crest precursors towards chondrogenic lineage through mTOR signaling and Wnt canonical signaling activities. In this Administrative Supplements, we propose a new collaboration with Dr. Jason Spence at the University of Michigan Medical School to directly address cellular and molecular mechanisms of how increased BMP signaling alters cell-fate specification in cranial neural crest cells. We will use single cell derived sphere formation and 3-dimentional organoid formation in culture to directly measure multi-potency of primary neural crest cells from early stage embryos as well as established stem cell lines from neural crests. Results from this collaboration will therefore provide better insights for molecular targets to restore normal cell fate determination ability and thus potential therapeutic treatment of human cases.
抽象的 颅缝早闭是一种使人衰弱的疾病,其特征是颅缝过早融合,导致 头骨形状异常。颅缝早闭的估计患病率为 1:2,500 活产儿,使其成为最常见的疾病之一 最常见的影响骨骼系统的先天性畸形。唯一的治疗方法是广泛的,并且 通常需要进行多次重建手术。母体R01的长期目标是定义分子 BMP 信号成分的功能获得性突变导致颅缝早闭的机制 啮齿动物模型。我们建立了一个条件小鼠模型,该模型显示神经嵴特异性增强 BMP 信号通过颅骨和缝合处的 BMP 1 型受体 BMPR1A 进行。这个模型是独特且重要的 由于:1) 观察到 p53 诱导的细胞凋亡上调,2) 异位软骨形成于 融合早于过早融合,表明颅缝早闭不是骨病而是干细胞疾病。 我们最近的数据强烈表明增强的 BMP-Smad 信号传导活动会影响细胞命运 通过 mTOR 信号传导对软骨形成谱系的多能神经嵴前体进行规范 和 Wnt 典型信号活动。在本行政补充文件中,我们提出了一项新的合作 与密歇根大学医学院的 Jason Spence 博士合作,直接解决细胞和分子问题 BMP 信号传导增加如何改变颅神经嵴细胞的细胞命运规范的机制。我们将 使用培养物中单细胞衍生的球体形成和三维类器官形成来直接测量 来自早期胚胎的原代神经嵴细胞以及建立的干细胞系的多能性 神经嵴。因此,这次合作的结果将为分子靶点提供更好的见解 恢复正常的细胞命运决定能力,从而对人类病例进行潜在的治疗。

项目成果

期刊论文数量(49)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Biocompatible Polymeric Analogues of DMSO Prepared by Atom Transfer Radical Polymerization.
  • DOI:
    10.1021/acs.biomac.6b01553
  • 发表时间:
    2017-02-13
  • 期刊:
  • 影响因子:
    6.2
  • 作者:
    Li S;Chung HS;Simakova A;Wang Z;Park S;Fu L;Cohen-Karni D;Averick S;Matyjaszewski K
  • 通讯作者:
    Matyjaszewski K
Local and Circulating Endothelial Cells Undergo Endothelial to Mesenchymal Transition (EndMT) in Response to Musculoskeletal Injury.
  • DOI:
    10.1038/srep32514
  • 发表时间:
    2016-09-12
  • 期刊:
  • 影响因子:
    4.6
  • 作者:
    Agarwal S;Loder S;Cholok D;Peterson J;Li J;Fireman D;Breuler C;Hsieh HS;Ranganathan K;Hwang C;Drake J;Li S;Chan CK;Longaker MT;Levi B
  • 通讯作者:
    Levi B
Characterization of Cells Isolated from Genetic and Trauma-Induced Heterotopic Ossification.
  • DOI:
    10.1371/journal.pone.0156253
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Agarwal S;Drake J;Qureshi AT;Loder S;Li S;Shigemori K;Peterson J;Cholok D;Forsberg JA;Mishina Y;Davis TA;Levi B
  • 通讯作者:
    Levi B
Bone morphogenetic protein signaling through ACVR1 and BMPR1A negatively regulates bone mass along with alterations in bone composition.
通过 ACVR1 和 BMPR1A 的骨形态发生蛋白信号传导负向调节骨量以及骨成分的改变
  • DOI:
    10.1016/j.jsb.2017.11.010
  • 发表时间:
    2018-03
  • 期刊:
  • 影响因子:
    3
  • 作者:
    Shi C;Mandair GS;Zhang H;Vanrenterghem GG;Ridella R;Takahashi A;Zhang Y;Kohn DH;Morris MD;Mishina Y;Sun H
  • 通讯作者:
    Sun H
Tissue Preparation and Immunostaining of Mouse Craniofacial Tissues and Undecalcified Bone.
  • DOI:
    10.3791/59113
  • 发表时间:
    2019-05
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Jingwen Yang;Haichun Pan;Y. Mishina
  • 通讯作者:
    Jingwen Yang;Haichun Pan;Y. Mishina
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Yuji MISHINA其他文献

Yuji MISHINA的其他文献

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{{ 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:
    10417330
  • 财政年份:
    2022
  • 资助金额:
    $ 21.2万
  • 项目类别:
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:
    $ 21.2万
  • 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:
    $ 21.2万
  • 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:
    $ 21.2万
  • 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:
    $ 21.2万
  • 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:
    $ 21.2万
  • 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:
    $ 21.2万
  • 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:
    $ 21.2万
  • 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:
    $ 21.2万
  • 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:
    $ 21.2万
  • 项目类别:

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