A novel cell-autonomous role for β-adrenergic receptor signaling in osteoclasts

破骨细胞中β-肾上腺素能受体信号传导的新型细胞自主作用

基本信息

  • 批准号:
    10608343
  • 负责人:
  • 金额:
    $ 5.04万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-06-01 至 2026-05-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT The overall goal of this supplemental research project is to support the career development of Rebecca Peters, who is a PhD candidate at the University of Maine Graduate School of Biomedical Sciences and Engineering. The sympathetic nervous system (SNS) is known to promote osteoclastogenesis via osteoblast-mediated RANKL production. However, recent work from our laboratory has demonstrated that β-blockers can limit osteoclast activity directly, without influencing RANKL production, in vitro and in mice treated with anabolic parathyroid hormone (PTH) therapy. Furthermore, the efficacy of the cardio-selective β-blocker atenolol to prevent osteoporosis is currently being tested in humans in the Atenolol to Prevent Osteoporosis (APO) trial, but mechanisms of efficacy with relationship to osteoclasts have not been studied in humans or mouse models. In the parent award, we are using genetic mouse models to test the hypotheses that β1AR and β2AR signaling in osteoclasts specifically promote osteoclast differentiation and function. However, the award does not examine the pharmacological properties of β-blockers that allow them to limit osteoclast differentiation directly, nor does it test the translatability of the findings to human osteoclast models. In this supplemental award, we will study the function of β1AR and β2AR in response to β-blockers in human and murine osteoclasts. We will also test whether our in vitro findings of atenolol-mediated suppression of osteoclast differentiation and bone resorption can be recapitulated in vivo. The proposed studies will not overlap with ongoing work on the parent award, but will complement and add translational significance to the findings. Supplement Specific Aim 1: Test the function of βARs in human osteoclasts in vitro. We have found that propranolol potentiates PTH-induced Ca2+ signaling in osteoblasts, however, β-blockers may have a distinct function in osteoclasts. Specifically, we hypothesize that β1AR and β2AR promote intracellular Ca2+-induced NFATc1 activity to support osteoclast differentiation, and that this is prevented by β-blockers. In this aim, we will use primary human peripheral blood mononuclear cell (PBMC) and murine bone marrow-derived osteoclasts to test this hypothesis. Supplement Specific Aim 2: Test the efficacy of atenolol to prevent bone resorption in vivo. We have preliminary data that atenolol also prevents human osteoclast differentiation in vitro, but whether it could be a potential co-therapy for osteoporosis treatment with PTH is unknown. Furthermore, whether atenolol would limit sympathetic nervous system-mediated resorption in vivo is unknown. We hypothesize that atenolol will limit resorption in both cases, indicating it could be clinically useful as an anti- resorptive therapy, whether or not SNS activity is high. To test whether atenolol will prevent bone resorption in the context of PTH therapy and elevated SNS tone, we will treat mice with atenolol and PTH or salbutamol (β2AR agonist, to mimic high SNS activity) and examine bone microarchitecture and resorption.
摘要

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)

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Katherine Jean Motyl其他文献

Katherine Jean Motyl的其他文献

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{{ truncateString('Katherine Jean Motyl', 18)}}的其他基金

A novel cell-autonomous role for β-adrenergic receptor signaling in osteoclasts
破骨细胞中β-肾上腺素能受体信号传导的新型细胞自主作用
  • 批准号:
    10414883
  • 财政年份:
    2021
  • 资助金额:
    $ 5.04万
  • 项目类别:
A novel cell-autonomous role for β-adrenergic receptor signaling in osteoclasts
破骨细胞中β-肾上腺素能受体信号传导的新型细胞自主作用
  • 批准号:
    10837441
  • 财政年份:
    2021
  • 资助金额:
    $ 5.04万
  • 项目类别:
A novel cell-autonomous role for β-adrenergic receptor signaling in osteoclasts
破骨细胞中β-肾上腺素能受体信号传导的新型细胞自主作用
  • 批准号:
    10633271
  • 财政年份:
    2021
  • 资助金额:
    $ 5.04万
  • 项目类别:
TRPM8 is a novel regulator of bone homeostasis through neural and cell-autonomous mechanisms
TRPM8 是一种通过神经和细胞自主机制调节骨稳态的新型调节剂
  • 批准号:
    9108599
  • 财政年份:
    2016
  • 资助金额:
    $ 5.04万
  • 项目类别:
TRPM8 is a novel regulator of bone homeostasis through neural and cell-autonomous mechanisms
TRPM8 是一种通过神经和细胞自主机制调节骨稳态的新型调节剂
  • 批准号:
    9923447
  • 财政年份:
    2016
  • 资助金额:
    $ 5.04万
  • 项目类别:
Mechanisms of Bone Loss from Administration of the Second-Generation Antipsychoti
第二代抗精神病药引起的骨质流失机制
  • 批准号:
    8329291
  • 财政年份:
    2011
  • 资助金额:
    $ 5.04万
  • 项目类别:
Mechanisms of Bone Loss from Administration of the Second-Generation Antipsychoti
第二代抗精神病药引起的骨质流失机制
  • 批准号:
    8516350
  • 财政年份:
    2011
  • 资助金额:
    $ 5.04万
  • 项目类别:
Mechanisms of bone loss from administration of the second-generation antipsychoti
第二代抗精神病药物引起的骨质流失机制
  • 批准号:
    8199942
  • 财政年份:
    2011
  • 资助金额:
    $ 5.04万
  • 项目类别:
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