miR-342, a novel glucocorticoid-responsive miRNA necessary for Foxp3+ regulatory T cell function

miR-342，一种新的糖皮质激素反应性 miRNA，是 Foxp3 调节 T 细胞功能所必需的

基本信息

批准号：
10671943
负责人：
Booki Min
金额：
$ 20万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-18 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10671943
关键词：
3&apos Untranslated Regions Affect Animal Model Area Autoimmunity Binding Biogenesis Cell Lineage Cell physiology Chronic Cytoplasm Defect Dexamethasone Disease Ensure Experimental Autoimmune Encephalomyelitis FOXP3 gene Gene Expression Generations Genes Glucocorticoids Homeostasis Human Human Genome Hypersensitivity Immune Immunity Immunosuppression Inflammation Inflammatory Inflammatory Response Lead Mediating Metabolic MicroRNAs Modeling Molecular Mus Nucleotides Patients Play Predisposition Proteins Refractory Regulation Regulatory T-Lymphocyte Reporting Resistance Ribonuclease III Role Serum Steroid Resistance Steroids Testing Therapeutic Effect Untranslated RNA allergic airway inflammation attenuation autoimmune inflammation exosome experimental study immune activation mortality mouse model novel novel therapeutic intervention overexpression programs response therapy development

项目摘要

Abstract Foxp3+ regulatory T cells (Treg) are the central regulators of immunity and tolerance. Defects in Treg generation and/or functions lead to lethal systemic autoimmune inflammation in both mice and human, demanding a tight regulation of Treg homeostasis. Determining factors capable of modulating Treg function is thus a subject of utmost importance. Among the factors is microRNA, a small non-coding RNA molecule known to regulate gene expression. There is plethora of evidence that miRNAs play a critical role in Treg generation and functions. However, our understanding the mechanisms by which Treg-derived miRNA modulates Treg functions is relatively limited. Glucocorticoids are the frontline treatment option for many inflammatory diseases, including autoimmunity and allergy. Despite the broad use, the precise immune suppressive mechanisms used by glucocorticoids remain largely elusive. We recently reported that Tregs are indispensable during glucocorticoid- induced treatment of chronic inflammation. Mechanistically, we uncovered that a novel miR-342 is induced by glucocorticoid stimulation in Tregs and that miR-342 targets metabolic regulator, Rictor, to control Treg metabolic programming. From the preliminary studies we also found that miR-342 is highly expressed in Tregs and that it is further enhanced by dexamethasone (Dex) stimulation. Interestingly, miR-342 expression in Tregs appears to be critical for Treg suppressive function. Moreover, miR-342 was also detected in the serum following Dex treatment. To our surprise, Dex-induced serum miR-342 was detected in steroid-sensitive but not in steroid- resistant inflammation. Based on the compelling evidence, we propose the hypothesis that miR-342 is a glucocorticoid-induced miRNA in Tregs that plays a regulatory role in Tregs’ ability to control inflammation. Two specific aims are proposed. First, we will determine the role of miR-342 in Treg functions. Two newly generated animal models in which Tregs lack or overexpress miR-342 will be used. Second, we will examine the role of Treg-derived miR-342 in steroid resistance. Identification of the mechanisms by which glucocorticoid-induced miR-342 regulates Treg functions will open novel opportunities to develop therapies applicable to manage severe inflammatory conditions including steroid resistance.

抽象的 Foxp3+ 调节性 T 细胞 (Treg) 是 Treg 生成缺陷的核心调节因子。和/或功能导致小鼠和人类致命的系统性自身免疫炎症，需要严格的因此，能够调节Treg功能的决定因素是Treg稳态的调节的一个主题。其中最重要的因素是 microRNA，一种已知可调节基因的小非编码 RNA 分子。大量证据表明 miRNA 在 Treg 的生成和功能中发挥着关键作用。然而，我们对 Treg 衍生的 miRNA 调节 Treg 功能的机制的理解是糖皮质激素是许多炎症性疾病的一线治疗选择，包括。尽管用途广泛，但其所使用的精确免疫抑制机制。我们最近报道说，糖皮质激素在很大程度上仍然难以捉摸。从机制上讲，我们发现一种新的 miR-342 是由 miR-342 诱导的。糖皮质激素对 Tregs 的刺激以及 miR-342 靶向代谢调节因子 Rictor 来控制 Treg 代谢从初步研究中我们还发现 miR-342 在 Tregs 中高表达，并且它地塞米松 (Dex) 刺激进一步增强了 Tregs 中的 miR-342 表达。此外，在 Dex 后的血清中也检测到了 miR-342。令我们惊讶的是，在类固醇敏感组中检测到了 Dex 诱导的血清 miR-342，但在类固醇敏感组中未检测到。基于令人信服的证据，我们提出 miR-342 是一种抗性炎症的假设。糖皮质激素诱导的 Tregs 中的 miRNA 在 Tregs 控制炎症的能力中发挥调节作用 2。首先，我们将确定 miR-342 在两个新生成的 Treg 功能中的作用。将使用 Tregs 缺乏或过度表达 miR-342 的动物模型其次，我们将检查 miR-342 的作用。 Treg 衍生的 miR-342 在类固醇抵抗中的作用机制的鉴定。 miR-342 调节 Treg 功能将为开发适用于治疗重症的疗法带来新的机会炎症状况，包括类固醇抵抗。