The Role of microRNAs in autoimmune disease

microRNA 在自身免疫性疾病中的作用

• 批准号: 8697657
• 负责人: Lukas T. Jeker
• 金额: $ 26.61万
• 依托单位: UNIVERSITY HOSPITAL BASEL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8697657
• 关键词: 3' Untranslated Regions; Ablation; Acute; Address; Adverse effects; Affect; Animal Model; Antibody Affinity; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Biochemical; Biological Assay; Biology; CD4 Positive T Lymphocytes; Cell Culture Techniques; Cell Differentiation process; Cell physiology; Cells; Clinical Trials; Complement; Cues; Cytokine Receptors; Cytokine Signaling; DNA Sequence; Data; Development; Disease; Disease model; Educational process of instructing; Environment; Equilibrium; Experimental Autoimmune Encephalomyelitis; Feedback; Functional RNA; Gene Expression; Gene Targeting; Genes; Genetic; Genome; Goals; Graft Rejection; Health Care Costs; Helper-Inducer T-Lymphocyte; Homeostasis; Immune; Immune response; Immune system; In Vitro; Infection; Insulin-Dependent Diabetes Mellitus; Interleukin-1; Knockout Mice; Laboratories; Lead; Malignant Neoplasms; Maps; Mediating; MicroRNAs; Modeling; Molecular; Multiple Sclerosis; Mus; Organ; Organ Transplantation; Pathway interactions; Patients; Population; Prevention; Publishing; Regulation; Regulator Genes; Regulatory T-Lymphocyte; Risk; Role; STAT3 gene; STAT5A gene; Shapes; Signal Transduction; Signal Transduction Pathway; T cell differentiation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Time; Work; arm; base; biological systems; cell type; cytokine; design; genetic analysis; genome-wide; improved; in vivo; inhibitor/antagonist; insight; mouse model; novel; pre-clinical; prevent; promoter; public health relevance; receptor expression; research study; response; therapeutic target; tool

DESCRIPTION (provided by applicant): This is a proposal to investigate the role of microRNAs in autoimmune diseases. Collectively, 5-10% of the western population is affected by some of the more than 80 autoimmune diseases that arise when the immune system attacks its own body. Current treatment options have limited efficacy, are expensive and have severe side effects such as increased risk for infections and cancer. In the long-term we aim to exploit microRNAs to control the immune system gone awry in patients with autoimmune diseases in order to restore immune homeostasis. Regulatory T cells (Treg) are cells of the immune system specialized to suppress immune responses. Due to their proven ability to prevent and even cure preclinical animal models of autoimmune diseases such as Type 1 diabetes and multiple sclerosis and their important role in preventing rejection of transplanted organs, Treg have entered clinical trials. In contrast, T follicular helper (TFH) cells provide classic "help" to B clls supporting the B cells' function to produce high-affinity antibodies. Both, dysregulation of Treg o TFH promote autoimmunity. microRNAs are regulators of gene expression only discovered relatively recently. Therefore our understanding of microRNA function in the immune system is very limited. Using in vivo gene ablation we showed the importance of the miRNA cluster miR-17-92 for Treg and TFH function. It is intriguing that miR-17- 92 sustains both, promoters and inhibitors of immune responses, respectively. [An important new finding is that miR-17-92 represses subset-inappropriate gene expression during TFH differentiation. Accordingly, we have refined the experiments to delineate in detail how miR-17-92 regulates T cell differentiation with a particular emphasis on the cell fate decision to differentiate into TFH rather than alternative T cell subsets. We propose that in the absence of miR-17-92 the cells respond to environmental cues they are not supposed to receive. We will characterize in depth the consequences of these inappropriate signals during TFH differentiation which will teach us what the normal function of miR-17-92 is. We will further assess if the same pathways are regulated by miR-17-92 in the functionally opposing Treg cells.] We will use cell culture assays and [mouse models used to generate TFH cells after infection and a model of acute autoimmune disease: experimental autoimmune encephalitis.] We are using mice that lack the miR-17-92 cluster in all T cells including TFH or only in Treg. The revised specific aims of this proposal ar: 1) [Exploring the role of miR-17-92 in sensing cytokines as a basis for cell fate determination] 2) Determine the molecular [basis] of miR-17-92 function in TFH and Treg.

描述（由申请人提供）：这是研究microRNA在自身免疫性疾病中的作用的建议。总体而言，当免疫系统攻击自己的身体时，有80多种自身免疫性疾病中有5-10％的人口受到了80多种自身免疫性疾病的影响。当前的治疗选择的功效有限，昂贵，并且具有严重的副作用，例如增加感染和癌症的风险。从长远来看，我们旨在利用microRNA来控制自身免疫性疾病患者的免疫系统，以恢复免疫稳态。调节性T细胞（TREG）是专门抑制免疫反应的免疫系统的细胞。由于它们具有预防甚至治愈自身免疫性疾病的临床前动物模型，例如1型糖尿病和多发性硬化症及其在防止拒绝移植器官中的重要作用，Treg已进入临床试验。相反，T卵泡辅助器（TFH）细胞为支持B细胞功能的B CLL提供了经典的“帮助”，以产生高亲和力的抗体。两者，Treg O TFH的失调促进自身免疫性。 microRNA是基因表达的调节剂，直到最近才发现。因此，我们对免疫系统中microRNA功能的理解非常有限。使用体内基因消融，我们显示了miRNA簇miR-17-92对Treg和TFH功能的重要性。令人着迷的是，miR-17-92分别维持免疫反应的启动子和抑制剂。 [一个重要的新发现是，miR-17-92在TFH分化过程中抑制了子集中适当的基因表达。因此，我们已经完善了实验，以详细描述miR-17-92如何调节T细胞分化，并特别强调细胞命运的决策以区分TFH而不是替代T细胞子集。我们建议，在没有miR-17-92的情况下，细胞对他们不应该接受的环境提示做出反应。我们将在TFH差异化过程中深入表征这些不适当信号的后果，这将教会我们miR-17-92的正常功能是什么。我们将进一步评估在功能相反的TREG细胞中MiR-17-92调节相同的途径。]我们将使用细胞培养分析和[用于感染后用于生成TFH细胞的小鼠模型和急性自身免疫性疾病的模型：实验性自身免疫性脑膜炎。]我们使用的小鼠缺乏Mir-17-92 Cluster在所有TF中的小鼠。该提案的修订特定目的AR：1）[探索miR-17-92在传感细胞因子作为细胞命运确定基础中的作用] 2）2） 确定TFH和Treg中miR-17-92功能的分子[基础]。