The role of miR-142 in regulatory T cell Development and function

miR-142 在调节性 T 细胞发育和功能中的作用

• 批准号: 10265552
• 负责人: Mark P Boldin
• 金额: $ 44万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-17 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10265552
• 关键词: Ablation; Affect; Antitumor Response; Attenuated; Autoimmune Diseases; Autoimmunity; Cancer Model; Cell Differentiation process; Cell Proliferation; Cell Therapy; Cell physiology; Cells; Cellular biology; Data; Defect; Development; Disease; Eragrostis; FOXP3 gene; Foundations; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic; Genetic Epistasis; Goals; High-Throughput Nucleotide Sequencing; Homeostasis; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunoprecipitation; Immunosuppression; Immunotherapy; Impairment; In Vitro; Individual; Infection; Interferon Type II; Knockout Mice; Knowledge; Lead; Link; Lymphoproliferative Disorders; Malignant Neoplasms; Mediating; MicroRNAs; Molecular; Molecular Target; Mus; Pathway interactions; Pharmacology; Play; Post-Transcriptional Regulation; Process; Production; Public Health; Regulation; Regulatory T-Lymphocyte; Research; Role; Route; Signal Transduction; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Tumor Immunity; Up-Regulation; Work; anti-tumor immune response; base; cancer immunotherapy; crosslink; experimental study; genetic element; immune self tolerance; in vitro testing; in vivo; innovation; insight; knock-down; loss of function; mouse model; novel; precursor cell; prevent; response; role model; small hairpin RNA; transcriptome; tumor; tumor growth

Project Summary Regulatory T (Treg) cells are vital for maintaining immunological self-tolerance and restraining overreactive immune responses against infection. Aberrant Treg cell activity is associated with autoimmune diseases and unproductive immune responses against tumors. An insufficient understanding of the molecular mechanisms that govern Treg cell biology is one of the critical barriers hampering development of effective Treg cell-based therapies for autoimmunity and cancer. Post-transcriptional control of gene expression by microRNAs (miRNAs) has recently emerged as an essential genetic element for Treg cell differentiation and function. Thus, the objective of this proposal is to gain better understanding of how individual miRNAs control central aspects of Treg cell biology. Closing of this knowledge gap may allow us to develop novel, targeted immunotherapies for treatment of Treg cell-mediated diseases. The focus of this proposal is to elucidate the function of miR-142 in Treg cells. Our results using genetic knockout mouse models indicate that miR-142 is an indispensable regulator of Treg cell- mediated immunosuppression. We uncovered two distinct roles for miR-142 in Treg cells: it promotes thymic Treg cell differentiation and positively regulates mature Treg cell homeostasis and suppressive activity. Moreover, we mechanistically linked the impaired function of mature miR-142-deficient Treg cells with excessive IFNg production and signaling, and identified several IFNg-associated genes as direct molecular targets of miR-142. Thus, our overall hypothesis is that miR-142 plays a crucial role in thymic Treg cell development and controls Treg cell abundance and functional activity. Furthermore, we posit that miR-142 regulates mature Treg cell homeostasis and suppressive function by attenuating production of and responsiveness to IFNg. We will test our central hypothesis with three specific aims. In Aim 1, we will investigate the role of miR-142 in thymic Treg cell development and define its mode of action. In Aim 2, we will determine the impact of inducible miR-142 depletion on Treg cell homeostasis and suppressive function in the context of antitumor immune response. Finally, in Aim 3, we will identify the molecular mechanism of miR-142-mediated control of Treg cell activity. To that end, we will determine how dysregulated IFNg signaling impacts the immunosuppressive activity and homeostasis of miR-142-deficient Treg cells. The proposed research is significant because it is expected to advance our understanding of miRNA-mediated mechanisms underlying the control of Treg cell function and immune tolerance. Additionally, this study may potentially lay a foundation for developing a novel miR-142-based therapeutic strategy for modulating Treg cell activity in cancer immunotherapy and autoimmune disease settings.

项目摘要 调节性T（Treg）细胞对于维持免疫自身耐受和抑制过度反应至关重要 对感染的免疫反应。异常Treg细胞活性与自身免疫性疾病相关， 对肿瘤无效的免疫反应。对分子机制的理解不足 控制Treg细胞生物学的基因是阻碍有效的基于Treg细胞的免疫治疗的发展的关键障碍之一。 自身免疫和癌症的治疗方法。microRNAs（miRNAs）对基因表达的转录后调控 最近作为Treg细胞分化和功能的必需遗传元件出现。因此，目标 这项提议的目的是更好地了解单个miRNAs如何控制Treg细胞的中心方面， 生物学缩小这一知识差距可能使我们能够开发新的，有针对性的免疫疗法用于治疗 Treg细胞介导的疾病。本研究的重点是阐明miR-142在Treg细胞中的功能。我们 使用基因敲除小鼠模型的结果表明，miR-142是Treg细胞不可或缺的调节因子， 介导的免疫抑制。我们发现了miR-142在Treg细胞中的两种不同作用： 细胞分化和正调节成熟Treg细胞稳态和抑制活性。而且我们 将成熟的miR-142缺陷型Treg细胞的功能受损与IFNg的过度产生机制联系起来 和信号传导，并确定了几个IFN相关基因作为miR-142的直接分子靶点。所以我们 总体假设是miR-142在胸腺Treg细胞发育中起关键作用，并控制Treg细胞 丰度和功能活性。此外，我们证实miR-142调节成熟Treg细胞的稳态， 以及通过减弱IFNg的产生和对IFNg的应答性来抑制功能。我们将测试我们的中央 有三个具体目标的假设。目的1：探讨miR-142在胸腺Treg细胞中的作用 发展并确定其行动模式。在目标2中，我们将确定可诱导的miR-142缺失的影响。 在抗肿瘤免疫应答的背景下对Treg细胞稳态和抑制功能的影响。最后，在Aim 3、明确miR-142调控Treg细胞活性的分子机制。为此，我们将 确定IFNg信号转导失调如何影响免疫抑制活性和体内平衡， miR-142缺陷型Treg细胞。拟议的研究是重要的，因为它有望推动我们的 了解miRNA介导的调节Treg细胞功能和免疫功能的机制 宽容此外，这项研究可能为开发一种新的基于miR-142的 用于在癌症免疫治疗和自身免疫性疾病环境中调节Treg细胞活性的治疗策略。