Molecular and cellular mechanisms of heterotopic ossification

异位骨化的分子和细胞机制

基本信息

  • 批准号:
    8538700
  • 负责人:
  • 金额:
    $ 5.98万
  • 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:
    2010-08-01 至 2015-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Heterotopic ossification (HO), the formation of ectopic endochondral bone in skeletal muscle and soft tissues, is a significant cause of morbidity from joint immobility and pain. The precise mechanisms responsible for HO are not known; however, its association with postsurgical and posttraumatic contexts suggests a process of disordered injury repair. Further insights into the causes of HO may be gained from a congenital HO syndrome, fibrodysplasia ossificans progressiva (FOP). FOP is caused by "constitutively-activating" mutations in the bone morphogenetic protein (BMP) type I receptor ALK2, which result in progressive and widespread joint ossifications triggered by minimal trauma or inflammation. Both FOP and acquired forms of HO lack effective therapies. In fact, there is significant evidence that both FOP and HO are caused by inappropriate activation of the BMP signaling pathway. It is not known how enhanced BMP signaling deviates the injury repair program, or which populations of cells mediate the effects of enhanced BMP signaling. To address these questions we have developed a mouse model of FOP in which a constitutively-active mutant form of ALK2 (caALK2) is inducibly expressed. Similar to affected humans, expression of this gene does not spontaneously induce HO, but vigorous ossification and joint fusion occur with additional stimuli of inflammation and muscle injury. Our subsequent studies with this model suggest that these caALK2 proteins may not be constitutively-active, as previously thought, but may sensitize cells to traditional ligand-mediated BMP signals. In Aim 1 of this grant, we will employ this model to discern the mechanisms by which caALK2 sensitizes cells to BMP signals, testing whether caALK2 requires ligand-mediated signaling or functions independently. To identify the cellular progenitors which mediate the effects of enhanced BMP signaling, and which contribute to the ectopic bone lesions, in Aim 2 we have targeted the expression of mutant caALK2 to several candidate progenitor lineages. Using a complement of cell-based, genetic targeting, and adoptive transfer techniques, we will systematically determine the impact of expressing caALK2 in compartments with known osteogenic potential, including skeletal muscle satellite cells, vascular pericytes, as well as bone-marrow derived lineages. In Aim 3, we examine the role of innate immune signaling in the development of ectopic bone in this model. Understanding how caALK2 mutations alter the consequences of BMP signaling could highlight novel molecular or cellular targets for management of HO. This proposal seeks to elucidate how enhanced BMP signaling impacts mesenchymal progenitors and governs adaptive and maladaptive osteogenesis at the interface of injury, inflammation, and regeneration.
描述(由申请人提供):异位骨化(HO),即骨骼肌和软组织中异位软骨内骨的形成,是关节不活动和疼痛发病的重要原因。 HO 的确切机制尚不清楚;然而,它与手术后和创伤后环境的关联表明了损伤修复过程的紊乱。通过先天性 HO 综合征——进行性骨化性纤维发育不良 (FOP),可以进一步了解 HO 的病因。 FOP 是由骨形态发生蛋白 (BMP) I 型受体 ALK2 的“组成性激活”突变引起的,这种突变会导致由最小的创伤或炎症引发的进行性和广泛的关节骨化。 FOP 和获得性 HO 都缺乏有效的治疗方法。事实上,有重要证据表明 FOP 和 HO 都是由 BMP 信号通路激活不当引起的。目前尚不清楚增强的 BMP 信号传导如何偏离损伤修复程序,或者哪些细胞群介导增强的 BMP 信号传导的作用。为了解决这些问题,我们开发了 FOP 小鼠模型,其中诱导表达 ALK2 (caALK2) 的组成型活性突变形式。与受影响的人类类似,该基因的表达不会自发诱导 HO,但在炎症和肌肉损伤的额外刺激下会发生剧烈的骨化和关节融合。我们随后对该模型的研究表明,这些 caALK2 蛋白可能并不像之前认为的那样具有组成型活性,但可能使细胞对传统配体介导的 BMP 信号敏感。在本次资助的目标 1 中,我们将利用该模型来辨别 caALK2 使细胞对 BMP 信号敏感的机制,测试 caALK2 是否需要配体介导的信号传导或独立发挥作用。为了鉴定介导增强的 BMP 信号传导作用并导致异位骨病变的细胞祖细胞,在目标 2 中,我们将突变体 caALK2 的表达靶向几个候选祖细胞谱系。使用基于细胞的遗传靶向和过继转移技术的补充,我们将系统地确定在具有已知成骨潜力的隔室中表达 caALK2 的影响,包括骨骼肌卫星细胞、血管周细胞以及骨髓衍生谱系。在目标 3 中,我们研究了先天免疫信号在该模型中异位骨发育中的作用。了解 caALK2 突变如何改变 BMP 信号传导的后果可以突出显示 HO 管理的新分子或细胞靶标。该提案旨在阐明增强的 BMP 信号传导如何影响间充质祖细胞并控制损伤、炎症和再生界面的适应性和适应不良成骨。

项目成果

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PAUL B YU其他文献

PAUL B YU的其他文献

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{{ truncateString('PAUL B YU', 18)}}的其他基金

Context-specific angiogenic signaling in the pulmonary vasculature
肺血管系统中特定的血管生成信号传导
  • 批准号:
    10770822
  • 财政年份:
    2021
  • 资助金额:
    $ 5.98万
  • 项目类别:
Context-specific angiogenic signaling in the pulmonary vasculature
肺血管系统中特定的血管生成信号传导
  • 批准号:
    10280040
  • 财政年份:
    2021
  • 资助金额:
    $ 5.98万
  • 项目类别:
Context-specific angiogenic signaling in the pulmonary vasculature
肺血管系统中特定的血管生成信号传导
  • 批准号:
    10450846
  • 财政年份:
    2021
  • 资助金额:
    $ 5.98万
  • 项目类别:
HLS- Cyclic CAR peptide: a targeted therapy for pulmonary hypertension
HLS-环状CAR肽:肺动脉高压的靶向治疗
  • 批准号:
    9347715
  • 财政年份:
    2017
  • 资助金额:
    $ 5.98万
  • 项目类别:
HLS- Cyclic CAR peptide: a targeted therapy for pulmonary hypertension
HLS-环状CAR肽:肺动脉高压的靶向治疗
  • 批准号:
    9789689
  • 财政年份:
    2017
  • 资助金额:
    $ 5.98万
  • 项目类别:
Molecular imaging of angiogenic activity in pulmonary arterial hypertension
肺动脉高压血管生成活性的分子成像
  • 批准号:
    9313927
  • 财政年份:
    2016
  • 资助金额:
    $ 5.98万
  • 项目类别:
Molecular and cellular mechanisms of heterotopic ossification
异位骨化的分子和细胞机制
  • 批准号:
    10238889
  • 财政年份:
    2010
  • 资助金额:
    $ 5.98万
  • 项目类别:
Molecular and cellular mechanisms of heterotopic ossification
异位骨化的分子和细胞机制
  • 批准号:
    8325423
  • 财政年份:
    2010
  • 资助金额:
    $ 5.98万
  • 项目类别:
Molecular and cellular mechanisms of heterotopic ossification
异位骨化的分子和细胞机制
  • 批准号:
    10685932
  • 财政年份:
    2010
  • 资助金额:
    $ 5.98万
  • 项目类别:
Molecular and cellular mechanisms of heterotopic ossification
异位骨化的分子和细胞机制
  • 批准号:
    10757487
  • 财政年份:
    2010
  • 资助金额:
    $ 5.98万
  • 项目类别:

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