Activin receptor-based therapies for musculoskeletal disease

基于激活素受体的肌肉骨骼疾病疗法

基本信息

  • 批准号:
    8220374
  • 负责人:
  • 金额:
    $ 38.28万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-09-21 至 2016-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Peak bone and skeletal muscle mass in mammals is highly correlated, suggesting the existence of common anabolic signaling networks in these anatomically adjacent tissues that promote their development. It has been widely assumed, that larger muscles stimulate increased skeletal acquisition indirectly, through force- generated mechanical signals, which transduce anabolic activity in the adjacent bone. Alternatively, these same signaling networks that control muscle mass might function directly in bone. While this latter concept is intuitively appealing, few basic studies have attempted to describe such a pathway. The studies in this application take direct aim at this problem and propose that the activin/myostatin signaling pathway constitutes a common mechanism that regulates the acquisition and maintenance of skeletal mass in a manner analogous to the well-defined activity of this pathway in muscle. In muscle, activation of activin receptor signaling by myostatin and related ligands negatively regulates muscle growth such that blocking signaling via genetic alterations or pharmacologic treatments profoundly increases in muscle mass. Consistent with this idea, we have found that functional components of the activin/myostatin receptors are abundantly expressed in osteoblasts. Further, we demonstrated that short-term treatment (4 IP injections) of a soluble ACVR2B receptor in wild-type mice rapidly (4 weeks) tripled trabecular bone mass, suggesting for the first time that activin signaling directly influences bone acquisition. Based upon these observations, we hypothesize that a subset of activin/myostatin molecules function through specific receptors in osteoblasts to directly inhibit bone acquisition, and that inhibition of such receptor signaling increases bone mass. In this project, we will test this hypothesis by characterizing the activin signaling components in bone and distinguishing them from those that operate in skeletal muscle. We will exploit new mouse models that lack selectively either ACVR2 or ACVR2B in bone to unambiguously identify skeletal actions of activin/myostatin signaling. In a second series of complementary studies, we will further test the significance of the activin pathway on bone and muscle mass, in wild type mice and models of age-related sarcopenia and osteopenia, by administration of soluble activin receptors. We expect the results from the studies proposed in this application will expedite clinical trials of activin receptor-based biologics to treat age-related bone and muscle loss in humans. PUBLIC HEALTH RELEVANCE: This project will use novel genetic mouse models to unambiguously define the direct actions of activin receptor signaling in skeletal development and maintenance. Further, we will evaluate the therapeutic efficacy of pharmacologically manipulating this pathway in a mouse model of age related bone and muscle loss. We anticipate that results from these studies will expedite clinical trials of activin receptor-based biologics to treat bone and muscle loss in humans.
描述(由申请人提供):哺乳动物的峰值骨质量和骨骼肌质量高度相关,表明在这些解剖学相邻组织中存在共同的合成代谢信号网络,促进其发育。人们普遍认为,较大的肌肉通过力产生的机械信号间接刺激骨骼获得的增加,该信号抑制邻近骨骼中的合成代谢活动。或者,这些控制肌肉质量的信号网络可能直接在骨骼中发挥作用。虽然后一个概念直观上很吸引人,但很少有基础研究试图描述这样的途径。本申请中的研究直接针对该问题,并提出激活素/肌肉生长抑制素信号传导途径构成了以类似于该途径在肌肉中的明确定义的活性的方式调节骨骼质量的获得和维持的共同机制。在肌肉中,肌生长抑制素和相关配体对激活素受体信号传导的激活负调节肌肉生长,使得通过遗传改变或药物治疗阻断信号传导显著增加肌肉质量。与这一想法一致,我们发现激活素/肌生长抑制素受体的功能组分在成骨细胞中大量表达。此外,我们证明了在野生型小鼠中短期治疗(4次IP注射)可溶性ACVR 2B受体使小梁骨量迅速(4周)增加两倍,这首次表明激活素信号传导直接影响骨获得。基于这些观察,我们假设激活素/肌肉生长抑制素分子的一个子集通过成骨细胞中的特异性受体发挥作用,直接抑制骨获得,并且抑制这种受体信号传导增加骨量。在这个项目中,我们将通过表征骨骼中的激活素信号成分并将其与骨骼肌中的激活素信号成分区分开来来验证这一假设。我们将利用在骨骼中选择性缺乏ACVR 2或ACVR 2B的新小鼠模型来明确鉴定激活素/肌肉生长抑制素信号传导的骨骼作用。在第二系列补充研究中,我们将通过给予可溶性激活素受体,在野生型小鼠和年龄相关性肌肉减少症和骨质减少症模型中进一步测试激活素途径对骨和肌肉质量的意义。我们预计,本申请中提出的研究结果将加快基于激活素受体的生物制剂的临床试验,以治疗人类与年龄相关的骨和肌肉损失。 公共卫生相关性:该项目将使用新的遗传小鼠模型来明确定义激活素受体信号传导在骨骼发育和维持中的直接作用。此外,我们将评估在年龄相关的骨和肌肉损失的小鼠模型中操纵该途径的治疗效果。我们预计,这些研究的结果将加快基于激活素受体的生物制剂治疗人类骨骼和肌肉损失的临床试验。

项目成果

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Douglas James DiGirolamo其他文献

Douglas James DiGirolamo的其他文献

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{{ truncateString('Douglas James DiGirolamo', 18)}}的其他基金

Activin receptor-based therapies for musculoskeletal disease
基于激活素受体的肌肉骨骼疾病疗法
  • 批准号:
    8900181
  • 财政年份:
    2011
  • 资助金额:
    $ 38.28万
  • 项目类别:
Activin receptor-based therapies for musculoskeletal disease
基于激活素受体的肌肉骨骼疾病疗法
  • 批准号:
    8700904
  • 财政年份:
    2011
  • 资助金额:
    $ 38.28万
  • 项目类别:
Activin receptor-based therapies for musculoskeletal disease
基于激活素受体的肌肉骨骼疾病疗法
  • 批准号:
    8512558
  • 财政年份:
    2011
  • 资助金额:
    $ 38.28万
  • 项目类别:
Activin receptor-based therapies for musculoskeletal disease
基于激活素受体的肌肉骨骼疾病疗法
  • 批准号:
    8706800
  • 财政年份:
    2011
  • 资助金额:
    $ 38.28万
  • 项目类别:
Activin receptor-based therapies for musculoskeletal disease
基于激活素受体的肌肉骨骼疾病疗法
  • 批准号:
    8335476
  • 财政年份:
    2011
  • 资助金额:
    $ 38.28万
  • 项目类别:
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