The role of GGPS1 and CYP1A1 mutations in atypical femoral fracture

GGPS1和CYP1A1突变在非典型股骨骨折中的作用

基本信息

  • 批准号:
    10055985
  • 负责人:
  • 金额:
    $ 20.34万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-08-01 至 2022-07-31
  • 项目状态:
    已结题

项目摘要

Abstract Atypical Femoral Fractures (AFFs) are a major clinical problem, both for the patients that suffers them and for the overall osteoporotic population because of their enormous impact on patients' willingness to be treated with effective osteoporosis medications. Also, although AFF has been associated with long-term bisphosphonates (BPs) treatment, a number of patients (up to 30%) who suffer AFF have never taken BPs. This observation suggests the presence of rare genetic mutations that form the basis of this condition and/or predispose certain patients to AFF by increasing their sensitivity to BPs. Identification of rare mutations that predispose to AFF, in particular after treatment with BPs, would permit the prevention of many of these fractures by selecting the appropriate treatment for such patients. Thus, understanding the genetic and molecular basis of AFF and diaphyseal fragility is of the utmost clinical importance. As of today, little is known about the pathogenesis of AFF and no animal model of AFF or of susceptibility to diaphyseal fractures is available. Notably, a recent potential breakthrough by Dr. Diez-Perez group may offer the opportunity to make initial steps in filling this knowledge gap. Specifically, exome sequencing in 3 sisters treated with BPs who suffered AFFs has identified mutations, shown or predicted to impair function, in 3 components of the mevalonate pathway, the very pathway targeted by BPs to inhibit bone resorption. Furthermore, 1 of 3 unrelated patients and a separate cohort showed mutations in CYP1A1, and mutations in GGPS and Farnesyl pyrophosphatase synthase (FPPS) have also been identified in 2 patients with Osteogenesis Imperfecta (OI) type V further suggesting a link between this pathway and bone fragility. The fact that this pathway is the target of nitrogen-containing bisphosphonates strongly suggests that these mutations, by mimicking/amplifying BPs action, may predispose patients to AFFs. Here, we will test the hypothesis that mutations in one or more of the key enzymes involved in the mevalonate pathway predispose to AFF, evidenced as increased diaphyseal fragility after BP treatment Aim 1) In vitro: Determine whether and how replication of the Ggps1 and/or Cyp1A1 mutations observed in the 3 sisters with AFF affect OC, OB and OCY differentiation and function and their responses to nitrogen-containing bisphosphonates. Aim 2) In vivo: Determine whether mice with heterozygous Ggps1 and/or Cyp1A1 deletion exhibit diaphyseal fragility before and/or after OVX and treatment with NBPs. Although mutations in this pathway probably constitute only a subset of the patients with AFF, this proposal may validate the concept that specific genetic alterations form the background of AFFs and provide the first, even though potentially imperfect, animal model to understand the mechanisms of these deleterious fractures.
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)

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 }}

ROLAND E BARON其他文献

ROLAND E BARON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('ROLAND E BARON', 18)}}的其他基金

The role of the osteocyte in responses to osteoporosis anabolic treatment in humans and mice
骨细胞在人类和小鼠骨质疏松合成代谢治疗反应中的作用
  • 批准号:
    10404416
  • 财政年份:
    2023
  • 资助金额:
    $ 20.34万
  • 项目类别:
Mechanism of action of PTH: New signaling components that regulate bone formation and bone marrow fat
PTH的作用机制:调节骨形成和骨髓脂肪的新信号成分
  • 批准号:
    10598064
  • 财政年份:
    2020
  • 资助金额:
    $ 20.34万
  • 项目类别:
Mechanism of action of PTH: New signaling components that regulate bone formation and bone marrow fat
PTH的作用机制:调节骨形成和骨髓脂肪的新信号成分
  • 批准号:
    10370393
  • 财政年份:
    2020
  • 资助金额:
    $ 20.34万
  • 项目类别:
Mechanism of action of PTH: New signaling components that regulate bone formation and bone marrow fat
PTH的作用机制:调节骨形成和骨髓脂肪的新信号成分
  • 批准号:
    10159214
  • 财政年份:
    2020
  • 资助金额:
    $ 20.34万
  • 项目类别:
The role of GGPS1 and CYP1A1 mutations in atypical femoral fracture
GGPS1和CYP1A1突变在非典型股骨骨折中的作用
  • 批准号:
    10222572
  • 财政年份:
    2020
  • 资助金额:
    $ 20.34万
  • 项目类别:
PTH resistance and marrow adipogenesis
PTH 抵抗和骨髓脂肪生成
  • 批准号:
    9979845
  • 财政年份:
    2017
  • 资助金额:
    $ 20.34万
  • 项目类别:
PTH resistance and marrow adipogenesis
PTH 抵抗和骨髓脂肪生成
  • 批准号:
    9401167
  • 财政年份:
    2017
  • 资助金额:
    $ 20.34万
  • 项目类别:
R-Spondin3 as a target for anabolic bone therapy
R-Spondin3 作为骨合成代谢治疗的靶点
  • 批准号:
    9478548
  • 财政年份:
    2014
  • 资助金额:
    $ 20.34万
  • 项目类别:
R-Spondin3 as a target for anabolic bone therapy
R-Spondin3 作为骨合成代谢治疗的靶点
  • 批准号:
    9250695
  • 财政年份:
    2014
  • 资助金额:
    $ 20.34万
  • 项目类别:
R-Spondin3 as a target for anabolic bone therapy
R-Spondin3 作为骨合成代谢治疗的靶点
  • 批准号:
    8693390
  • 财政年份:
    2014
  • 资助金额:
    $ 20.34万
  • 项目类别:

相似海外基金

How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 20.34万
  • 项目类别:
    Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 20.34万
  • 项目类别:
    Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 20.34万
  • 项目类别:
    Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 20.34万
  • 项目类别:
    Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 20.34万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 20.34万
  • 项目类别:
    Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 20.34万
  • 项目类别:
    Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 20.34万
  • 项目类别:
    Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
  • 批准号:
    23K00129
  • 财政年份:
    2023
  • 资助金额:
    $ 20.34万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
  • 批准号:
    2883985
  • 财政年份:
    2023
  • 资助金额:
    $ 20.34万
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了