MicroRNA regulation of chronic inflammation during aging
MicroRNA对衰老过程中慢性炎症的调节
基本信息
- 批准号:10817445
- 负责人:
- 金额:$ 8万
- 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:2022-09-01 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Abstract: Parent Grant -1R01AG079477-01
Chronic inflammation, referred to as "inflammaging", is a risk factor for many age-related chronic conditions (e.g.
diabetes, cancer, frailty). Aberrant immune responses may be linked to inflammatory-mediated metabolic and
functional disorders but many mechanistic gaps exist. Among recently appreciated regulators of inflammaging
are microRNAs (miRNAs). One example of which is the anti-inflammatory miR-146a, where we and others have
shown that mice deficient in this miRNA succumb to a life-shortening chronic inflammation that involves clinically
relevant comorbidities (1-6). Moreover, deletion of miR-155 in T cells significantly extends the lifespan of miR-
146a·1
• mice which points to a vital role for T cell expressed miR-155 in this context including CD4+ T follicular
helper (Tfh) cells (3, 5). We have recently expanded our analyses of this critical process by investigating novel
pathways in aging T cells that are regulated by miR-155 during inflammaging. By conducting single cell RNA
Sequencing (scRNA-Seq) we have identified three gene programs that are counter-regulated by miR-146a and
miR-155 in aged T cells that have not been previously examined in this context. These include aerobic glycolysis,
chemokine production, and senescence associated secretory phenotype (SASP) factors. Additional preliminary
data stemming from initial exploration of these pathways have pointed us to a novel, age-associated
inflammatory cos+ T cell subset (Taa cells) that is GZMK"CD8" and that expands in both mice and humans (7),
and that is regulated by miR-155. Based on these preliminary data, we will carry out the following research aims
in an effort to gain substantial new insights into T cell-dependent mechanisms that drive inflammaging and that
are regulated by miRNAs. We will also uniquely extend these analyses to young and older adults in efforts to
translate our findings to humans. 1) Determine the functional roles of miR-155-induced GZMK+CD8+ T cells
during inflammaging. 2) Determine the molecular and metabolic mechanisms underlying miR-155
functions in T cells during inflammaging. 3) Determine if Taa and Tfh cells and their miR-155 levels in
older adults correlate with markers of chronic, low-grade inflammation, insulin sensitivity, and muscle
strength. We anticipate that this work will unveil key cellular and molecular mechanisms by which miRNAs play
pivotal roles in regulating lifespan through their influence on T cell-mediated, age-dependent chronic
inflammation. As a result, therapeutically actionable targets will emerge with the potential to limit age-associated
human inflammatory diseases that continue to rapidly gain in prevalence in our society.
摘要:母基金-1R01AG079477-01
慢性炎症,被称为“炎症”,是许多与年龄相关的慢性病症(例如,
糖尿病、癌症、虚弱)。异常的免疫应答可能与炎症介导的代谢和
功能障碍,但存在许多机制空白。在最近受到重视的炎症调节因子中,
microRNAs(miRNAs)其中一个例子是抗炎的miR-146 a,我们和其他人已经研究了它。
表明缺乏这种miRNA的小鼠会死于缩短寿命的慢性炎症,
相关合并症(1-6)。此外,T细胞中miR-155的缺失显著延长了miR-155的寿命。
146a·1
·小鼠,其指出T细胞表达的miR-155在这种情况下的重要作用,包括CD 4 + T滤泡细胞
辅助(Tfh)细胞(3,5)。最近,我们通过研究新的
在炎症过程中,衰老T细胞中由miR-155调节的途径。通过引导单细胞RNA
测序(scRNA-Seq),我们已经确定了三个由miR-146 a和miR-146 b反向调节的基因程序。
miR-155在衰老T细胞中的作用,以前没有在这种情况下进行过研究。这些包括有氧糖酵解,
趋化因子产生和衰老相关分泌表型(SASP)因子。补充初步
对这些途径的初步探索所产生的数据为我们指出了一种新的、与年龄相关的
炎性cos+ T细胞亚群(Taa细胞),其是GZMK“CD 8”并在小鼠和人中扩增(7),
并且受miR-155调控。基于这些初步数据,我们将开展以下研究目标
为了获得对驱动炎症的T细胞依赖性机制的实质性新认识,
是由miRNAs调控的。我们还将独特地将这些分析扩展到年轻人和老年人,
将我们的发现应用到人类身上1)确定miR-155诱导的GZMK+ CD 8 + T细胞的功能作用
在炎症期间。2)确定miR-155的分子和代谢机制
在炎症过程中T细胞的功能。3)确定Taa和Tfh细胞及其miR-155水平是否在
老年人与慢性、低度炎症、胰岛素敏感性和肌肉萎缩的标志物相关。
实力我们预计这项工作将揭示miRNAs发挥作用的关键细胞和分子机制,
通过影响T细胞介导的、年龄依赖性的慢性炎症,在调节寿命方面发挥关键作用
炎症因此,治疗上可行的目标将出现,有可能限制年龄相关的
人类炎症性疾病在我们的社会中继续迅速流行。
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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Micah J Drummond其他文献
Micah J Drummond的其他文献
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{{ truncateString('Micah J Drummond', 18)}}的其他基金
Regulation of macrophage metabolism in aged muscle during recovery
衰老肌肉恢复过程中巨噬细胞代谢的调节
- 批准号:
10622569 - 财政年份:2022
- 资助金额:
$ 8万 - 项目类别:
Regulation of macrophage metabolism in aged muscle during recovery
衰老肌肉恢复过程中巨噬细胞代谢的调节
- 批准号:
10460028 - 财政年份:2022
- 资助金额:
$ 8万 - 项目类别:
MicroRNA regulation of chronic inflammation during aging
MicroRNA对衰老过程中慢性炎症的调节
- 批准号:
10531053 - 财政年份:2022
- 资助金额:
$ 8万 - 项目类别:
Targeting macrophage polarization to optimize muscle regrowth from disuse atrophy
靶向巨噬细胞极化以优化废用性萎缩的肌肉再生
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10228828 - 财政年份:2020
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Role of immune cells on the growth and recovery of aging muscle
免疫细胞对衰老肌肉生长和恢复的作用
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10197500 - 财政年份:2019
- 资助金额:
$ 8万 - 项目类别:
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