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: 10462770
• 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/10462770
• 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.

项目总结