Regulatory mechanisms of miR-19b, a novel mediator of T cell autoimmunity

T细胞自身免疫的新型介质miR-19b的调节机制

基本信息

批准号：
8234916
负责人：
Qijing Li
金额：
$ 25.24万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-12-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8234916
关键词：
Acute Antigens Autoimmune Diseases Autoimmune Process Autoimmunity Biochemical Biology Brain CD4 Positive T Lymphocytes Cell Lineage Cells Cellular biology Cessation of life Chemical Engineering Complex Cytokine Signaling Data Development Disease Elements Engineering Enhancers Epigenetic Process Etiology Functional RNA Gene Cluster Genes Goals Human Immune Immune response Immune system Immunotherapy In Vitro Individual Inflammation Inflammatory Response Interleukin-17 Knowledge Link Lymphoid Maintenance Major Histocompatibility Complex Malignant Neoplasms Mediating Mediator of activation protein Membrane Methyl-CpG-Binding Protein 2 MicroRNAs Molecular Mutation Nature Oligonucleotides Organ Pathway interactions Pattern Peptides Phase Phosphoric Monoester Hydrolases Phosphotransferases Physiological Play Process Production Proteins Receptor Activation Regulation Research Personnel Rett Syndrome Role Signal Pathway Signal Transduction Staging T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte Th1 Cells Therapeutic Intervention Tumor Immunity Uncertainty Virus autoreactive T cell base combat immunoregulation in vivo inhibitor/antagonist loss of function member neoplastic cell nervous system disorder neuron development novel novel therapeutics overexpression response scaffold

项目摘要

DESCRIPTION (provided by applicant): Regulatory mechanisms of miR-19b, a novel mediator of T cell autoimmunity: The inappropriate activation and differentiation of CD4 T cells elicits and orchestrates the onset and progression of a wide range of autoimmune diseases. Understanding CD4 T cells' intrinsic regulatory mechanisms has direct implications for the development of novel therapeutics to treat these diseases. While the protein-based signal transduction machinery downstream of T cell antigen recognition has been thoroughly studied, we have recently become aware of a novel and crucial element dictating T cell fate-microRNA (miRNA). mir-17-92 is a gene cluster encoding six different miRNAs, whose important tumor-cell-intrinsic roles in cancer have been well established. However, we have recently discovered that the mir-17-92 cluster also potentiates anti-tumor immunity in a T-cell-intrinsic manner. Furthermore, our preliminary studies indicate that mir-17-92 dictates the progression of CD4 T cell-mediated autoimmunity, principally through the activity of the cluster's mir-19b component. We aim to discover the molecular mechanism underpinning miR-19b's pro- autoimmune regulatory function, and thereby to establish miR-19b as a potential target for therapy of autoimmune diseases. PUBLIC HEALTH RELEVANCE: In this project, we are focusing on the previously unknown role of microRNA miR-19b in immunoregulation. miR-19b controls CD4 T cells' antigen response by modulating multiple signaling pathways, indicating that it may be a promising target for restoring tolerance under autoimmune conditions. One of the primary targets of this microRNA is MeCP2, the causal factor of the devastating Rett Syndrome, which provides a new angle to understand the etiology of this neuronal development disease. In addition to fundamentally advancing the fields of miRNA biology and T cell biology, this study is very likely to provide new candidate targets for oligonucleotide-based immunotherapy to combat autoimmune diseases.

描述（由申请人提供）：MiR-19b的调节机制，一种新型T细胞自身免疫的介体：CD4 T细胞的不适当激活和分化引发并策划了广泛的自身免疫性疾病的发作和进展。了解CD4 T细胞的固有调节机制对治疗这些疾病的新疗法的发展具有直接的影响。虽然已经对T细胞抗原识别的下游基于蛋白质的信号转导机械进行了彻底的研究，但我们最近意识到了一种新颖而关键的元素决定了T细胞命运 - 麦克罗纳（MiRNA）。 miR-17-92是一个编码六种不同miRNA的基因簇，其在癌症中的重要肿瘤细胞内在作用已得到很好的确定。但是，我们最近发现，miR-17-92簇还以T细胞内在的方式增强了抗肿瘤免疫力。此外，我们的初步研究表明，miR-17-92决定了CD4 T细胞介导的自身免疫的进展，主要是通过簇的miR-19b成分的活性。我们的目的是发现基于miR-19b的促进自身免疫调节功能的分子机制，从而建立miR-19b作为自身免疫性疾病治疗的潜在靶标。公共卫生相关性：在这个项目中，我们专注于MicroRNA miR-19b在免疫调节中的作用。 miR-19b通过调节多个信号通路来控制CD4 T细胞的抗原反应，这表明它可能是在自身免疫条件下恢复公差的有希望的目标。该microRNA的主要靶标之一是MECP2，MECP2是毁灭性RETT综合征的因子，该因素提供了一个新的角度来了解这种神经元发育疾病的病因。除了从根本上推进miRNA生物学和T细胞生物学领域外，这项研究很可能为基于寡核苷酸的免疫疗法提供新的候选靶标，以抗击自身免疫性疾病。