Function of Regulator of G protein signaling in aging skeleton

G蛋白信号调节因子在骨骼衰老中的作用

基本信息

  • 批准号:
    9294321
  • 负责人:
  • 金额:
    $ 36.79万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-08-01 至 2019-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Age-associated osteoporosis is a major health problem, which is characterized by an imbalance in bone remodeling and metabolism due to the increase of osteoclastogenesis and activity with age. The current treatment options have been constrained with lower response rates or side-effects and ineffectively tackle the burden and heterogeneity of osteoporosis. Further progress in establishing successful treatment urgently requires a clearer understanding of the mechanisms of osteoclast (OC) differentiation and bone remodeling with age. Evidences have documented that RANKL -evoked Ca2+ oscillations play a switch-on role in the activation of PLC� and NFATc1, and OC differentiation. Further study showed that FcR� and DAP 12 regulate the phosphorylation of PLC�, which is the critical component involved in the RANKL-induced Ca2+ oscillations- NFATc1 pathway. Despite these new insights, it remains unclear how RANKL evokes the essential Ca2+ oscillations that triggers NFATc1 activation and OC differentiation, and it is unknown whether and how this mechanism is involved in age-associated bone loss. Our recent research demonstrated that Regulator of G protein signaling protein 12 (RGS12) was prominently expressed during OC differentiation and that RGS12 expression was significantly increased with increasing age. Knockdown of RGS12 expression inhibited Ca2+ oscillations, NFATc1 expression and OC differentiation. Deletion of RGS12 from hematopoietic/early OC lineage cells (RGS12 / /cre) led to a significantly increase of bone mass, and this increase of bone mass was protected from age-associated bone loss in RGS12 / /cre mice. We also found that loss of RGS12 in mice decreased OC number and levels of marrow adipogenesis with age. Based on these results, we hypothesize that age-associated bone remodeling and metabolism requires RGS12 expression and function, and RGS12 is a critical regulator in controlling Ca2+ oscillation and OC differentiation during aging. We will test the hypothesis through the following two specific aims. In Aim 1, we will reveal the function of RGS12 in OC differentiation and function during aging through characterization of the phenotypes and pathomechanism of RGS12 conditional knockout mice. We will analyze bone phenotypes in young (6 months (m)), mid-aged (14m) and aged (24m) mice to determine how deletion of RGS12 in early and late OC lineage cells affect postnatal age-associated bone metabolism by using Mx1-cre and Cathepsin K-Cre mice. We will further characterize in vitro of OCs derived from aging RGS12 / /cre mice and determine the contribution of mesenchymal lineage cells to the OCs and skeletal phenotype in aging RGS12 / /cre mice. In Aim 2, we will elucidate the mechanism of RGS12 interactions that confer specificity of Ca2+ oscillation and OCs with age by characterizing pathomechanism and pathways, RGS12 domain functions and its heterodimerization partners. The goal of this project is to discover the role and mechanism of RGS12 in OC differentiation and activation in pathologic age condition, and provide new and more effective therapeutic targets to age-associated osteoporosis and other bone diseases.
描述(申请人提供):年龄相关性骨质疏松症是一个主要的健康问题,其特征是由于破骨细胞的生成和活动随着年龄的增加而导致骨重建和代谢的失衡。目前的治疗方案受限于较低的应答率或副作用,并且不能有效地应对骨质疏松的负担和异质性。在建立成功的治疗方法方面的进一步进展迫切需要更清楚地了解破骨细胞(OC)分化和随年龄变化的骨重建的机制。有证据表明,RANKL诱导的钙振荡在PLC�和NFATc1的激活以及OC分化中起着启动作用。进一步的研究表明,FcR�和DAP12调节�的磷酸化,这是RANKL诱导的钙振荡-NFATc1途径中的关键成分。尽管有这些新的见解,但RANKL如何引发必要的钙振荡,触发NFATc1激活和OC分化,以及这一机制是否以及如何参与与年龄相关的骨丢失,目前尚不清楚。我们最近的研究表明,G蛋白信号蛋白12调节因子(RGS12)在OC分化过程中显著表达,并且随着年龄的增长,RGS12的表达显著增加。RGS12表达下调可抑制细胞内钙离子振荡、NFATc1表达和OC分化。从造血系/早期OC细胞(RGS12//cre)中缺失RGS12导致骨量显著增加,这种增加的骨量在RGS12//cre小鼠中受到保护,不受年龄相关性骨丢失的影响。我们还发现,随着年龄的增长,RGS12基因的缺失会降低小鼠的OC数量和骨髓脂肪生成水平。基于这些结果,我们假设与年龄相关的骨重建和代谢需要RGS12的表达和功能,RGS12是控制衰老过程中钙振荡和OC分化的关键调节因子。我们将通过以下两个具体目标来检验这一假设。目的1通过对RGS12条件性基因敲除小鼠的表型和发病机制的研究,揭示RGS12在OC分化和衰老过程中的作用。我们将分析年轻(6个月)、中年(14个月)和老年(24个月)小鼠的骨表型,以确定早期和晚期OC谱系细胞中RGS12的缺失如何影响出生后年龄相关的骨代谢,方法是使用Mx1-cre和组织蛋白酶K-Cre小鼠。我们将在体外进一步鉴定老龄RGS12//cre小鼠来源的OCs,并确定间充质系细胞对衰老RGS12//cre小鼠OCS和骨骼表型的贡献。在目标2中,我们将通过研究RGS12的致病机制和途径、RGS12结构域的功能以及它的异二聚体伙伴来阐明RGS12相互作用赋予钙离子振荡和OCS与年龄的特异性的机制。本课题的目的是揭示RGS12在病理性年龄条件下OC分化和激活中的作用和机制,为老年性骨质疏松症等骨病的治疗提供新的、更有效的靶点。

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 }}

SHUYING YANG其他文献

SHUYING YANG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('SHUYING YANG', 18)}}的其他基金

Regulation of skeletal development and homeostasis by IFT protein
IFT 蛋白对骨骼发育和稳态的调节
  • 批准号:
    9292979
  • 财政年份:
    2016
  • 资助金额:
    $ 36.79万
  • 项目类别:
Role of RGS12, a Regulator of G protein Signaling, in Bone Remodeling
RGS12(G 蛋白信号传导调节剂)在骨重塑中的作用
  • 批准号:
    9294325
  • 财政年份:
    2016
  • 资助金额:
    $ 36.79万
  • 项目类别:
Regulation of skeletal development and homeostasis by IFT protein
IFT 蛋白对骨骼发育和稳态的调节
  • 批准号:
    9271951
  • 财政年份:
    2016
  • 资助金额:
    $ 36.79万
  • 项目类别:
Function of Regulator of G protein signaling in aging skeleton
G蛋白信号调节因子在骨骼衰老中的作用
  • 批准号:
    8767760
  • 财政年份:
    2014
  • 资助金额:
    $ 36.79万
  • 项目类别:
Regulation of skeletal development and homeostasis by IFT protein
IFT 蛋白对骨骼发育和稳态的调节
  • 批准号:
    8697956
  • 财政年份:
    2014
  • 资助金额:
    $ 36.79万
  • 项目类别:
Function of Regulator of G protein signaling in aging skeleton
G蛋白信号调节因子在骨骼衰老中的作用
  • 批准号:
    9346657
  • 财政年份:
    2014
  • 资助金额:
    $ 36.79万
  • 项目类别:
Role of RGS12, a Regulator of G protein Signaling, in Bone Remodeling
RGS12(G 蛋白信号传导调节剂)在骨重塑中的作用
  • 批准号:
    8842593
  • 财政年份:
    2014
  • 资助金额:
    $ 36.79万
  • 项目类别:
The role of IFT80 in bone formation
IFT80 在骨形成中的作用
  • 批准号:
    8432452
  • 财政年份:
    2012
  • 资助金额:
    $ 36.79万
  • 项目类别:
The role of IFT80 in bone formation
IFT80 在骨形成中的作用
  • 批准号:
    8288401
  • 财政年份:
    2012
  • 资助金额:
    $ 36.79万
  • 项目类别:
The role of IFT80 in bone formation
IFT80 在骨形成中的作用
  • 批准号:
    8626360
  • 财政年份:
    2012
  • 资助金额:
    $ 36.79万
  • 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:
    $ 36.79万
  • 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:
    $ 36.79万
  • 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:
    $ 36.79万
  • 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:
    $ 36.79万
  • 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:
    $ 36.79万
  • 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:
    $ 36.79万
  • 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:
    $ 36.79万
  • 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:
    $ 36.79万
  • 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:
    $ 36.79万
  • 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:
    $ 36.79万
  • 项目类别:
    Miscellaneous Programs
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了