Targeting the HIF-2 Signaling Pathway as a Radioprotective Strategy for Bone

将 HIF-2 信号通路作为骨辐射防护策略

基本信息

  • 批准号:
    10665782
  • 负责人:
  • 金额:
    $ 35.42万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-15 至 2027-06-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY While radiation therapy effectively eliminates malignant cells, damage to healthy tissue surrounding tumors remains a persistent clinical issue. Indeed, cancer patients who receive radiation treatment have an increased risk for fracture when compared to those who undergo the same treatment regimen but who are not subjected to radiotherapy. Unfortunately, the use of antiresorptive agents such as bisphosphates does not significantly reduce insufficiency fractures for this patient population. For these reasons, our long-term goal is to identify unique cellular and molecular mechanisms that can be therapeutically exploited for the radioprotection of bone. Notably, the bone microenvironment (BME) is characterized by low oxygen tension or hypoxia. In response to this external stimulus, many cell types in the BME activate hypoxia inducible factor (HIF) signaling to facilitate cell survival. While activation of the HIF signaling pathway is required to maintain healthy bone, the contribution of hypoxia/HIF signaling during radiation induced bone damage has not been well defined. Intriguingly, we show irradiated bones show a decrease in multipotent mesenchymal progenitors (MMPs) when compared to non- irradiated controls. Moreover, preliminary data shows that MMPs are found in hypoxic regions and respond to hypoxia by stabilizing HIF-2. Strikingly, while conditional ablation of HIF-2 in a population of MMPs did not alter bone homeostasis, it did serve to protect against bone loss after radiation exposure. For these reasons, our overarching hypothesis is that genetic and pharmacological inhibition of HIF-2 will serve as a radioprotective mechanism to ameliorate bone damage after radiation exposure, in part, by maintaining the number of MMPs that can functionally contribute to bone after stress induced damage. To test our hypothesis, we will utilize a combination of genetically engineered mouse models, in vitro cell culture experiments, and novel pharmacological approaches to inhibit the HIF-2 signaling pathway in the BME. Currently, there are no FDA approved agents to mitigate radiation induced bone loss, hence these studies will not only expand our fundamental knowledge of bone biology but will also fill an unmet clinical need to identify therapeutic targets which will ameliorate bone damage after radiotherapy.
项目摘要 虽然放射治疗有效地消除了恶性细胞, 仍然是一个持续的临床问题。事实上,接受放射治疗的癌症患者 与接受相同治疗方案但未接受治疗的患者相比, 到放疗。不幸的是,抗吸收剂如二磷酸盐的使用并不显著地 减少该患者人群的功能不全骨折。因此,我们的长期目标是确定 独特的细胞和分子机制,可以在治疗上用于骨的辐射防护。 值得注意的是,骨微环境(BME)的特征在于低氧张力或缺氧。响应于 在这种外部刺激下,BME中的许多细胞类型激活缺氧诱导因子(HIF)信号传导, 细胞存活虽然HIF信号通路的激活是维持健康骨骼所必需的,但HIF信号通路的作用是促进骨形成。 低氧/HIF信号在辐射诱导的骨损伤过程中的作用还没有很好的定义。有趣的是,我们发现 与未照射的骨相比,照射的骨显示多能间充质祖细胞(MMPs)减少。 辐照对照。此外,初步数据显示,MMPs存在于缺氧区域,并对缺氧反应。 通过稳定HIF-2来实现缺氧。引人注目的是,尽管在MMPs人群中有条件地切除HIF-2并没有改变 骨稳态,它确实有助于防止辐射暴露后的骨丢失。由于这些原因,我们 总体假设是HIF-2的遗传和药理学抑制将作为辐射防护剂, 部分通过维持MMPs的数量来改善辐射暴露后骨损伤的机制 在应力引起的损伤后可以在功能上对骨有贡献。为了验证我们的假设,我们将使用 基因工程小鼠模型、体外细胞培养实验和新的 本发明涉及抑制BME中HIF-2信号传导途径的药理学方法。目前,没有FDA 批准的药物,以减轻辐射引起的骨丢失,因此这些研究不仅将扩大我们的研究范围, 骨生物学的基础知识,但也将填补一个未满足的临床需要,以确定治疗目标 其将改善放射治疗后的骨损伤。

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 }}

Colleen Wu其他文献

Colleen Wu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 }}

相似国自然基金

相似海外基金

Recruitment of brown adipocytes in visceral white adipose tissue by fibroblast growth factor 8b
成纤维细胞生长因子 8b 将棕色脂肪细胞募集到内脏白色脂肪组织中
  • 批准号:
    321208980
  • 财政年份:
    2016
  • 资助金额:
    $ 35.42万
  • 项目类别:
    Research Grants
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
  • 批准号:
    8827438
  • 财政年份:
    2014
  • 资助金额:
    $ 35.42万
  • 项目类别:
Induction of brown-like adipocytes in white adipose tissue by food-derived factors
食物源性因子在白色脂肪组织中诱导棕色样脂肪细胞
  • 批准号:
    26450168
  • 财政年份:
    2014
  • 资助金额:
    $ 35.42万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
WAT-on-a-chip - Development of a micofluidic, microphysiologic in vitro adipose tissue model for high-throughput drug screening based on hiPSC-derived adipocytes.
WAT-on-a-chip - 开发微流体、微生理体外脂肪组织模型,用于基于 hiPSC 衍生脂肪细胞的高通量药物筛选。
  • 批准号:
    257256526
  • 财政年份:
    2014
  • 资助金额:
    $ 35.42万
  • 项目类别:
    Research Fellowships
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
  • 批准号:
    8828181
  • 财政年份:
    2013
  • 资助金额:
    $ 35.42万
  • 项目类别:
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
  • 批准号:
    8520690
  • 财政年份:
    2013
  • 资助金额:
    $ 35.42万
  • 项目类别:
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
  • 批准号:
    8629741
  • 财政年份:
    2013
  • 资助金额:
    $ 35.42万
  • 项目类别:
Effect of exercise training on formation of brite adipocytes within white adipose tissue
运动训练对白色脂肪组织内脂肪细胞形成的影响
  • 批准号:
    23700778
  • 财政年份:
    2011
  • 资助金额:
    $ 35.42万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
Investigation for the mechanisms of the emergence of brown adipocytes in white adipose tissue
白色脂肪组织中棕色脂肪细胞出现机制的研究
  • 批准号:
    21780261
  • 财政年份:
    2009
  • 资助金额:
    $ 35.42万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
LOUISIANA COBRE: P1: INDUCE THERMOGENIC BROWN ADIPOCYTES IN WHITE ADIPOSE TISSUE
路易斯安那 COBRE:P1:在白色脂肪组织中诱导产热棕色脂肪细胞
  • 批准号:
    7610781
  • 财政年份:
    2007
  • 资助金额:
    $ 35.42万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了