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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)：一种新的T细胞自身免疫介体miR-19b的调节机制：CD4T细胞的不适当激活和分化导致并协调了一系列自身免疫性疾病的发生和发展。了解CD4T细胞的内在调节机制对开发治疗这些疾病的新疗法具有直接意义。虽然T细胞抗原识别下游基于蛋白质的信号转导机制已经被深入研究，但我们最近意识到决定T细胞命运的一个新的关键元件-microRNA(MiRNA)。MiR-17-92是一个编码六种不同miRNAs的基因簇，其在肿瘤细胞中的重要内在作用已被证实。然而，我们最近发现，mir-17-92簇也以T细胞固有的方式增强抗肿瘤免疫。此外，我们的初步研究表明，mir-17-92决定了CD4T细胞介导的自身免疫的进展，主要是通过该簇的mir-19b成分的活性。我们的目标是发现miR-19b促自身免疫调节功能的分子机制，从而建立miR-19b作为治疗自身免疫性疾病的潜在靶点。公共卫生相关性：在这个项目中，我们关注的是microRNA miR-19b在免疫调节中以前未知的作用。MIR-19b通过调节多条信号通路控制CD4T细胞的抗原反应，表明它可能是在自身免疫条件下恢复耐受的一个有前途的靶点。这种microRNA的主要靶点之一是MeCP2，这是破坏性Rett综合征的原因因素，这为理解这种神经元发育疾病的病因提供了一个新的角度。除了从根本上推进miRNA生物学和T细胞生物学领域，这项研究很可能为基于寡核苷酸的免疫治疗提供新的候选靶点，以对抗自身免疫性疾病。