The Role of RBC Reactive Oxygen Species in Regulating Thrombotic Events During Aging

红细胞活性氧在调节衰老过程中血栓事件中的作用

基本信息

  • 批准号:
    10293939
  • 负责人:
  • 金额:
    $ 44.36万
  • 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:
    2021-08-15 至 2026-04-30
  • 项目状态:
    未结题

项目摘要

The Role of RBC Reactive Oxygen Species in Regulating Thrombotic Events During Aging Abstract: Seventy percent of mid-life stage (older) adults have already been diagnosed with at least one chronic condition. As such, venous thrombosis/thromboembolism (VT/E) is up to 7 times higher in adults over 55 years old, compared to a younger cohort. VT/E affect over one million Americans per year. In light of an increasing life expectancy, development of chronic diseases will become a greater health care issue. Despite this, the key risk factors contributing to increased risks for developing chronic diseases in older adults remain unclear. Thus, it is critical to identify drug-targetable causative mechanisms predisposing older adults to develop chronic diseases to reduce these risks. Oxidative stress is one of the hallmarks of aging, and a critical contributor to VT/E. In aging, while studies have extensively focused on oxidative stress in the vasculature, the role of oxidative stress in RBCs predisposing to VT/E has been neglected. We now provide preliminary evidence for a unique activated pathogenic mechanism intrinsic to RBCs that can initiate prothrombotic pathways in older adults. RBCs from older (58-68 years old) adults show excessive reactive oxygen species (ROS) mediating adhesive and prothrombotic processes in vitro compared to RBCs from younger (21-30 years old) adults. Increased RBC ROS were generated by NADPH oxidases (Noxs), and involved RBC GRK2 activation. This suggests that aging adversely modifies RBC adhesive and prothrombotic potentials through GRK2/Nox/ROS . We also discovered that small non-coding nucleolar RNAs (snoRNAs) from the Rpl13a gene locus regulate RBC ROS-mediated thrombus formation in aged mouse models in vivo. We hypothesize that RBC GRK2/Nox/ROS pathway in older adults activates RBC adhesive and prothrombotic phenotypes, by which venous thrombosis (VT) may occur in the aging population. We further hypothesize that this ROS pathway is regulated by RBC Rpl13a snoRNAs, and that inhibition of this pathway can reduce adhesive and procoagulant processes. To test our hypotheses, we propose to use blood samples from older (55-65 years old) and younger (21- 30 years old) adults, and aged mouse models with the equivalent of human ages, and determine: SA1) that RBC GRK2/Nox are involved in the molecular and cellular bases by which VT may occur in aging, and that targeting GRK2/Nox pharmacologically and genetically will reduce RBC adhesive and prothrombotic potentials; SA2) that Rpl13a snoRNAs regulate RBC ROS pathway and downstream events in aging; and SA3) the transcriptomic changes dysregulating RBC ROS levels triggering procoagulant pathway in aging. Our studies will provide novel insights into the exact RBC mechanisms contributing to prothrombotic pathway in aging, and may identify novel targetable RBC anomalies to prevent prothrombotic cascade activation, thus laying the foundation for more rational therapeutic strategies that better reduce the risks for VT/E in mid-life stage adults with exaggerated oxidative stress.
红细胞活性氧在衰老过程中对血栓形成的调节作用 摘要: 70%的中年(老年)成年人已经被诊断出患有至少一种慢性疾病。 条件因此,静脉血栓形成/血栓栓塞(VT/E)在55岁以上的成年人中高达7倍 与年轻人相比,VT/E每年影响超过一百万美国人。根据一项 随着预期寿命的增加,慢性病的发展将成为一个更大的卫生保健问题。 尽管如此,导致老年人患慢性病风险增加的主要风险因素 成年人还不清楚。因此,确定药物靶向致病机制至关重要, 老年人发展慢性疾病,以减少这些风险。氧化应激是 老化,也是VT/E的关键因素。在衰老过程中,虽然研究广泛关注氧化 由于血管系统中的应激,氧化应激在诱发VT/E的RBC中的作用被忽视。 我们现在提供了一个独特的激活致病机制内在的红细胞的初步证据 可以启动老年人的血栓前通路。来自老年人(58-68岁)的RBC显示 过量活性氧(ROS)介导体外粘附和血栓形成过程 与年轻人(21-30岁)的RBC相比。增加的RBC ROS产生于 NADPH氧化酶(Noxs),并参与红细胞GRK 2活化。这表明,衰老 通过GRK 2/Nox/ROS改变RBC粘附和促血栓形成的潜力。我们还发现 来自Rpl 13 a基因座的小的非编码核仁RNA(snoRNA)调节RBC ROS介导的 体内老年小鼠模型中的血栓形成。我们假设红细胞GRK 2/Nox/ROS通路 在老年人中激活RBC粘附和血栓形成前表型, 可能发生在老年人身上。我们进一步假设,这种ROS途径是由红细胞调节的。 Rpl 13 a snoRNA,并且该途径的抑制可以减少粘附和促凝血过程。 为了验证我们的假设,我们建议使用老年人(55-65岁)和年轻人(21- 65岁)的血液样本。 30岁)成年人和与人年龄相当的老年小鼠模型,并确定: RBC GRK 2/Nox参与了VT可能在衰老中发生的分子和细胞基础, 并且靶向GRK 2/Nox激酶和基因将减少RBC粘附, 促血栓形成潜力; SA 2)Rpl 13 a snoRNA调节RBC ROS途径和下游 SA 3)转录组学变化使RBC ROS水平失调, 促凝血途径在衰老中的作用我们的研究将为RBC的确切机制提供新的见解 有助于促血栓通路老化,并可能确定新的靶向红细胞异常, 阻止血栓前级联激活,从而为更合理的治疗奠定基础 更好地降低中年阶段氧化应激过度成年人VT/E风险的策略。

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 }}

Rahima Zennadi其他文献

Rahima Zennadi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('Rahima Zennadi', 18)}}的其他基金

Oxidative stress mechanisms regulating gamma-globin gene transcription in sickle cell disease
镰状细胞病中调节伽马珠蛋白基因转录的氧化应激机制
  • 批准号:
    10649412
  • 财政年份:
    2022
  • 资助金额:
    $ 44.36万
  • 项目类别:
Oxidative stress mechanisms regulating gamma-globin gene transcription in sickle cell disease
镰状细胞病中调节伽马珠蛋白基因转录的氧化应激机制
  • 批准号:
    10340421
  • 财政年份:
    2022
  • 资助金额:
    $ 44.36万
  • 项目类别:
The Role of RBC Reactive Oxygen Species in Regulating Thrombotic Events During Aging
红细胞活性氧在调节衰老过程中血栓事件中的作用
  • 批准号:
    10622574
  • 财政年份:
    2021
  • 资助金额:
    $ 44.36万
  • 项目类别:
The Role of RBC Reactive Oxygen Species in Regulating Thrombotic Events During Aging
红细胞活性氧在调节衰老过程中血栓事件中的作用
  • 批准号:
    10461852
  • 财政年份:
    2021
  • 资助金额:
    $ 44.36万
  • 项目类别:
Activation of Sickle Red Cell Adhesion
镰状红细胞粘附的激活
  • 批准号:
    6676784
  • 财政年份:
    2003
  • 资助金额:
    $ 44.36万
  • 项目类别:
Activation of Sickle Red Cell Adhesion
镰状红细胞粘附的激活
  • 批准号:
    6899320
  • 财政年份:
    2003
  • 资助金额:
    $ 44.36万
  • 项目类别:
Activation of Sickle Red Cell Adhesion
镰状红细胞粘附的激活
  • 批准号:
    6793200
  • 财政年份:
    2003
  • 资助金额:
    $ 44.36万
  • 项目类别:
Activation of Sickle Red Cell Adhesion
镰状红细胞粘附的激活
  • 批准号:
    7070077
  • 财政年份:
    2003
  • 资助金额:
    $ 44.36万
  • 项目类别:

相似海外基金

I-Corps: Translation Potential of Peptidic Ensembles as Novel Bio-adhesives
I-Corps:肽整体作为新型生物粘合剂的转化潜力
  • 批准号:
    2409620
  • 财政年份:
    2024
  • 资助金额:
    $ 44.36万
  • 项目类别:
    Standard Grant
Architectural design of active adhesives
活性粘合剂的结构设计
  • 批准号:
    2403716
  • 财政年份:
    2024
  • 资助金额:
    $ 44.36万
  • 项目类别:
    Standard Grant
Design of non-swellable adhesives for brain surgery using cyclodextrin inclusion polymer
使用环糊精包合物聚合物脑外科不可溶胀粘合剂的设计
  • 批准号:
    23H01718
  • 财政年份:
    2023
  • 资助金额:
    $ 44.36万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Meta-material adhesives for improved performance and functionalisation of bondlines
超材料粘合剂可提高粘合层的性能和功能化
  • 批准号:
    EP/W019450/1
  • 财政年份:
    2023
  • 资助金额:
    $ 44.36万
  • 项目类别:
    Fellowship
Light-propelled dental adhesives with enhanced bonding capability
具有增强粘合能力的光驱动牙科粘合剂
  • 批准号:
    10741660
  • 财政年份:
    2023
  • 资助金额:
    $ 44.36万
  • 项目类别:
DMREF: Accelerating the Design of Adhesives with Nanoscale Control of Thermomechanical Properties
DMREF:通过热机械性能的纳米级控制加速粘合剂的设计
  • 批准号:
    2323317
  • 财政年份:
    2023
  • 资助金额:
    $ 44.36万
  • 项目类别:
    Continuing Grant
Mag-Cure: A novel method for magnetically induced bonding and de-bonding of thermoset adhesives in the Automotive Industry
Mag-Cure:汽车行业中热固性粘合剂磁感应粘合和脱粘的新方法
  • 批准号:
    10062336
  • 财政年份:
    2023
  • 资助金额:
    $ 44.36万
  • 项目类别:
    Collaborative R&D
Biodegradable, Biocompatible Pressure Sensitive Adhesives
可生物降解、生物相容性压敏粘合剂
  • 批准号:
    10677869
  • 财政年份:
    2022
  • 资助金额:
    $ 44.36万
  • 项目类别:
Poly(glycerol carbonate) pressure sensitive adhesives for the in vivo closure of alveolar pleural fistulae
用于体内闭合肺泡胸膜瘘的聚(甘油碳酸酯)压敏粘合剂
  • 批准号:
    10746743
  • 财政年份:
    2022
  • 资助金额:
    $ 44.36万
  • 项目类别:
Mechanisms of Blood Clot Adhesion and the Design of New Wet Adhesives
血凝块粘附机制及新型湿粘合剂的设计
  • 批准号:
    RGPIN-2018-04918
  • 财政年份:
    2022
  • 资助金额:
    $ 44.36万
  • 项目类别:
    Discovery Grants Program - Individual
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了