Role of miRNA Dysregulation on T Cell Differentiation and Function in MS

miRNA 失调对 MS 中 T 细胞分化和功能的作用

• 批准号: 10551306
• 负责人: Amy E Lovett-Racke
• 金额: $ 44.12万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-03 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551306
• 关键词: Affect; Autoimmune; Autoimmune Diseases; CD4 Positive T Lymphocytes; CNS autoimmunity; Cell Differentiation process; Cell physiology; Cells; Complement; Data; Defect; Development; Disease; Disease Progression; Disease susceptibility; Experimental Autoimmune Encephalomyelitis; Failure; Functional disorder; Gene Expression; Genes; Human; Immune; In Vitro; Individual; Inflammatory; Interleukin-6; Laboratories; Mediating; MicroRNAs; Modeling; Multiple Sclerosis; Mus; Nerve Degeneration; Neurologic Deficit; Pathology; Pathway interactions; Persons; Play; Population; Predisposition; Proteins; RNA Interference Pathway; Receptor Signaling; Regulatory T-Lymphocyte; Risk; Risk Factors; Role; Signal Pathway; Signal Transduction; T cell differentiation; T-Lymphocyte; Testing; Th1 Cells; Th2 Cells; Transforming Growth Factor beta; autoreactive T cell; central nervous system demyelinating disorder; cytokine; disability; experimental study; in vivo; inhibitor; innovation; memory CD4 T lymphocyte; mouse model; multiple sclerosis patient; novel; overexpression; prevent; therapeutic miRNA; therapeutic target; young adult

Abstract Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) which can result in severe neurological deficits. The cause of the disease is unknown, the immune and neurodegenerative mechanisms underlying the pathophysiology of the disease are poorly understood, and current therapies are only partially effective at slowing disease progression. There is a tremendous need to investigate novel mechanisms that may be contributing to disease susceptibility and the pathophysiology of this disease. To this end, my laboratory has performed a large miRNA profiling study on naïve and effector/memory CD4 T cell in untreated MS patients to determine if miRNA may contribute to disease susceptibility or progression. MiRNA negatively regulate gene expression via the RNA interference pathway, and thus play a key role modulating the level of specific proteins in cells. We have identified at least two pathways that are altered in MS patients that may contribute to their susceptibility to develop MS. First, miRNAs targeting components of the Th2 cell differentiation pathway were elevated in MS patients T cells, skewing differentiation into pro-inflammatory Th1 cells. Second, miRNAs targeting the TGFβ signaling pathway limited the differentiation of regulatory T cells. Thus, the defects observed in MS patients CD4 T cells may be at least partially mediated by miRNA dysregulation. In this proposal, we will address the following questions. Aim 1: Are MS patients’ CD4 T cells defective in their ability to differentiate into Tregs in a miRNA-dependent manner? Preliminary data indicates that naïve CD4 T cells from MS patients fail to efficiently differentiate into Tregs. Using miRNA inhibitors, we will determine if this failure to differentiate into Tregs is dependent on specific miRNAs over-expressed in MS patients and whether Treg differentiation can be normalized MS patients’ naïve CD4 T cells. Aim 2: How does over-expression of MS-associated miRNAs affect the development and progression of CNS autoimmunity in a mouse model? Using EAE, the role of miRNAs that target CD4 T cell differentiation into effector and regulatory T cells will be analyzed in vivo to complement the human in vitro experiments. Aim 3: Can expression level of miR-128, which targets both effector and regulatory CD4+ T cells, modulate the risk of CNS autoimmunity? We found that miR-128 targets proteins in the Th2 and TGFβ signaling pathways, promoting the differentiation of Th1 cells and preventing the development of Tregs. Using CD4-specific miR-128-/- mice and mice overexpressing miR-128 in CD4 T cells, we will determine if loss of miR-128 in CD4 T cells minimizes susceptibility to CNS autoimmunity, normalizes CD4 T cell differentiation into effector and regulatory cells, and thus, is a potential therapeutic target to correct both effector and regulatory T cell defects in MS. In contrast, we will use mice overexpressing miR-128 in CD4 T cells to determine if miR-128 is sufficient to skew CD4 T cell differentiation and enhance the risk of developing CNS autoimmunity. This study will test the hypothesis that miRNA dysregulation in naïve CD4+ T cells is an underlying risk factor in CNS autoimmunity that can be therapeutically targeted to normalize effector and regulatory CD4 T cell function. If our hypothesis is correct, miRNA-based therapies may not only prevent CNS autoimmunity in susceptible individuals, but ameliorate autoreactive T cells in patients with MS.

抽象的 多发性硬化症（MS）是一种免疫介导的中枢神经系统（CNS）的脱髓鞘疾病 在严重缺陷中。 该疾病的病理生理学的基本知名度很差，咖喱仅在部分有效 疾病进展减慢。 疾病的敏感性和该疾病的病理生理学。 对未治疗的MS患者的幼稚和效应子/记忆CD4 T细胞的分析研究，以确定miRNA是否可以贡献 疾病的敏感性或进展。 因此，在细胞中的特定蛋白质水平调节了关键作用。 在MS患者中发生了改变，可能有助于其发展女士的概念，首先，miRNA针对组件 MS患者T细胞的Th2细胞分化途径升高，将分化偏离促炎性 Th1细胞。 MS患者观察到的缺陷CD4 T细胞可能至少是由miRNA失调介导的。 我们将解决以下问题1：MS患者的CD4 T细胞有缺陷 以miRNA依赖性方式进入Treg？ 有效地使用miRNA抑制剂区分了Treg，我们将确定降级为Tregs 取决于MS患者中过表达的特定miRNA，以及是否可以将Treg分化归一化MS 患者的幼稚CD4 T细胞2：MS相关的miRNA的过表达如何影响 使用EAE的CNS自动免疫的进展，MiRNA的作用 在效应子和调节性T细胞中将在体内bear缩，以补充人类的体外实验 miR-128的表达水平，靶向效应子和调节性CD4+ T细胞，模块CNS的风险 自身免疫性？ 使用CD4特异性miR-128 - / - 小鼠和小鼠的Th1细胞的区分并防止Treg的发展 在CD4 T细胞中过表达miR-128，我们将确定CD4 T细胞中miR-128的损失是否可以最大程度地减少对CNS的敏感性 自身免疫性，将CD4 T细胞的分化标准化为Ento Ento Ento Condulatorate细胞，因此 纠正MS中的效应子和调节剂T细胞缺陷。 在CD4 T细胞中以确定miR-128是否为超级 CNS自身免疫性。 CNS自身免疫性的危险因素可以 功能，如果我们的假设是正确的，基于miRNA 个体，但在患有MS的患者中，氨氨酸盐自身反应性T细胞。