MicroRNA regulation of chronic inflammation during aging

摘要：Parent Grant-1R01AG079477-01 慢性炎症，称为“发炎”，是许多与年龄相关的慢性疾病的危险因素。 糖尿病、癌症、虚弱)。异常的免疫反应可能与炎症介导的代谢和 功能障碍，但存在许多机械缺口。在最近受到好评的炎症监管机构中 是microRNAs(MiRNAs)。其中一个例子是抗炎的miR-146a，我们和其他人在那里 研究表明，缺乏这种miRNA的小鼠会死于一种缩短生命的慢性炎症，这在临床上是 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 ·表明T细胞起重要作用的小鼠在这种情况下表达miR-155，包括CD4T滤泡 辅助(TFH)细胞(3，5)。我们最近通过研究小说来扩展我们对这一关键过程的分析 炎症过程中受miR-155调控的衰老T细胞中的通路。通过引导单细胞RNA 测序(scRNA-Seq)我们已经确定了三个受miR-146a和miR-146a逆调控的基因程序 在老化的T细胞中存在MIR-155，这些T细胞以前没有在这方面进行过检查。其中包括有氧糖酵解， 趋化因子的产生和衰老相关的分泌表型(SASP)因子。额外的初步报告 从对这些通路的初步探索中获得的数据为我们指出了一种与年龄相关的新颖的 炎症性COS T细胞亚群(TAA细胞)，即GZMK“CD8”，在小鼠和人类中均可扩张(7)， 这是由miR-155调节的。基于这些初步数据，我们将开展以下研究目标 为了获得对T细胞依赖机制的实质性新见解，T细胞依赖机制驱动炎症和 受miRNAs调控。我们还将独特地将这些分析扩展到年轻人和老年人，努力 将我们的发现转化为人类。1)确定miR-155诱导的GZMK CD8 T细胞的功能 在发炎过程中。2)确定miR-155的分子和代谢机制 T细胞在炎症过程中的功能。3)确定TAA和TFH细胞及其miR-155水平在 老年人与慢性低度炎症、胰岛素敏感性和肌肉相关 力量。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。 通过对T细胞介导的年龄依赖性慢性疾病的影响，在调节寿命方面发挥关键作用 发炎。因此，治疗上可操作的靶点将出现，有可能限制与年龄相关的 人类炎症性疾病在我们的社会中继续迅速流行。

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.