MicroRNA regulation of chronic inflammation during aging

MicroRNA对衰老过程中慢性炎症的调节

• 批准号: 10817445
• 负责人: Micah J Drummond
• 金额: $ 8万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10817445
• 关键词: 3-Dimensional; Age; Aging; Cellular Metabolic Process; Chronic; Disease; Inflammation; Inflammatory; MicroRNAs; Molecular; Myeloid Cells; Phenotype; Regulation; T cell regulation; Work; age related; new therapeutic target; parent grant; recruit; senescence

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：父母赠款-1R01AG079477-01 慢性炎症，称为“炎症”，是许多与年龄有关的慢性疾病的危险因素（例如 糖尿病，癌症，脆弱）。 功能障碍但有许多机械差距。 是microRNA（mirnas）。 表明在这种慢性生命的慢性中，小鼠的界限涉及临床 相关合并症（1-6）。 146a 1 •在这种情况下，小鼠指出T细胞表达miR-155的至关重要的作用，包括CD4+ T卵泡 助手（TFH）细胞（3，5）。 在炎症过程中由miR -155重新调节的老化TC细胞中的途径。 测序（SCRNA-SEQ）我们已经确定了由miR-146a和 在这种情况下，MiR-155仇恨未经审查。 趋化因子和衰老相关的分泌表型（SASP）因素 来自对这些途径的初始探索的数据使我们指出了一种新颖的，与年龄相结合的 炎症性COS+ T细胞子集（TAA细胞）是GZMK“ CD8”，并且在小鼠和人类中都扩展（7）， 这是由MiR-155定期的。 为了获得大量新的新见解，以使T细胞深度维护机制驱动炎症，并 由miRNA定期。 将我们的发现转换为人类。 在炎症期间。2）确定miR-155的分子和代谢机制 炎症过程中T细胞的功能。 老年人与慢性，低度炎症，胰岛素敏感性和肌肉的标记相关 力量。 通过对T细胞介导的年龄依赖性慢性的影响来调节寿命的关键作用 炎症。 人类炎症疾病在我们社会中继续迅速增加的人类炎症疾病。