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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

基本信息

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
项目类别：
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

项目摘要

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) 脱髓鞘疾病，可导致严重的神经功能缺损。发病原因不明，免疫和神经退行性机制人们对这种疾病的病理生理学机制知之甚少，目前的治疗方法仅部分有效减缓疾病进展。非常需要研究可能有助于疾病易感性和该疾病的病理生理学。为此，我的实验室进行了大miRNA 对未经治疗的多发性硬化症患者的初始 CD4 T 细胞和效应/记忆 CD4 T 细胞进行分析研究，以确定 miRNA 是否可能发挥作用疾病易感性或进展。 miRNA 通过 RNA 干扰途径负向调节基因表达，从而在调节细胞中特定蛋白质的水平方面发挥关键作用。我们已经确定了至少两条途径 MS 患者的基因发生改变，可能导致他们更容易患 MS。一、miRNA靶向成分 MS 患者 T 细胞的 Th2 细胞分化途径升高，偏向分化为促炎细胞 Th1细胞。其次，针对TGFβ信号通路的miRNA限制了调节性T细胞的分化。因此，在 MS 患者中观察到的 CD4 T 细胞缺陷可能至少部分是由 miRNA 失调介导的。在这个提案中，我们将讨论以下问题。目标 1：多发性硬化症患者的 CD4 T 细胞分化能力是否存在缺陷以 miRNA 依赖性方式转化为 Tregs？初步数据表明，来自多发性硬化症患者的初始 CD4 T 细胞无法有效分化为Tregs。使用 miRNA 抑制剂，我们将确定这种未能分化为 Tregs 的情况是否是由取决于多发性硬化症患者中过度表达的特定 miRNA 以及 Treg 分化是否可以使多发性硬化症正常化患者的初始 CD4 T 细胞。目标 2：MS 相关 miRNA 的过度表达如何影响发育和发育小鼠模型中中枢神经系统自身免疫的进展？使用 EAE，靶向 CD4 T 细胞分化的 miRNA 的作用效应T细胞和调节性T细胞将在体内进行分析，以补充人体体外实验。目标 3：可以 miR-128 的表达水平同时针对效应细胞和调节性 CD4+ T 细胞，可调节 CNS 风险自身免疫？我们发现 miR-128 靶向 Th2 和 TGFβ 信号通路中的蛋白，促进 Th1 细胞的分化并阻止 Tregs 的发育。使用 CD4 特异性 miR-128-/- 小鼠和小鼠在 CD4 T 细胞中过度表达 miR-128，我们将确定 CD4 T 细胞中 miR-128 的缺失是否会最大限度地降低对 CNS 的易感性自身免疫，使 CD4 T 细胞分化正常化为效应细胞和调节细胞，因此是一种潜在的治疗方法旨在纠正 MS 中的效应 T 细胞和调节 T 细胞缺陷。相反，我们将使用过度表达 miR-128 的小鼠在 CD4 T 细胞中确定 miR-128 是否足以扭曲 CD4 T 细胞分化并增加发生风险中枢神经系统自身免疫。这项研究将检验以下假设：幼稚 CD4+ T 细胞中的 miRNA 失调是潜在的 CNS 自身免疫中的危险因素，可作为治疗目标以使效应细胞和调节性 CD4 T 细胞正常化功能。如果我们的假设是正确的，基于 miRNA 的疗法不仅可以预防易感人群的中枢神经系统自身免疫个体，但改善多发性硬化症患者的自身反应性 T 细胞。