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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：
10328903
负责人：
Amy E Lovett-Racke
金额：
$ 47.08万
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/10328903
关键词：
Address 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 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 receptor 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.

摘要多发性硬化（MS）是一种免疫介导的中枢神经系统（CNS）脱髓鞘疾病，其可导致严重的神经系统缺陷这种疾病的原因是未知的，免疫和神经退行性机制疾病的病理生理学基础知之甚少，目前的治疗方法仅部分有效，减缓疾病进展。有一个巨大的需要调查新的机制，可能有助于疾病易感性和这种疾病的病理生理学。为此，我的实验室进行了一个大型的miRNA 对未经治疗的MS患者中的幼稚和效应/记忆CD 4 T细胞进行分析研究，以确定miRNA是否可能起作用疾病的易感性或进展。miRNA通过RNA干扰途径负调控基因表达，并因此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种途径，在MS患者中改变，这可能有助于他们发展MS的易感性。在MS患者中，Th 2细胞分化途径的T细胞升高， Th 1细胞其次，靶向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CD 4 T细胞缺陷可能至少部分由miRNA失调介导。在这一提议中，我们将讨论以下问题。目的1：MS患者的CD 4 T细胞是否存在分化能力缺陷以依赖于miRNA的方式转化为TcR？初步数据表明，来自MS患者的幼稚CD 4 T细胞不能有效地分化为THP。使用miRNA抑制剂，我们将确定这种不能分化成TGFAP的现象是否是取决于MS患者中过表达的特定miRNA以及Treg分化是否可以正常化MS 患者的初始CD 4 T细胞。目的2：多发性硬化相关miRNAs的过度表达如何影响多发性硬化的发生和发展？小鼠模型中中枢神经系统自身免疫的进展？使用EAE，靶向CD 4 T细胞分化的miRNA的作用将在体内分析转化为效应T细胞和调节T细胞以补充人体外实验。目标3：可以靶向效应和调节性CD 4 + T细胞的miR-128的表达水平调节CNS风险自身免疫我们发现miR-128靶向Th 2和TGFβ信号通路中的蛋白质，促进细胞凋亡。 Th 1细胞的分化和防止TcB的发展。使用CD 4特异性miR-128-/-小鼠和小鼠在CD 4 T细胞中过表达miR-128，我们将确定CD 4 T细胞中miR-128的缺失是否使对CNS的易感性最小化。自身免疫使CD 4 T细胞分化为效应细胞和调节细胞正常化，因此是一种潜在的治疗方法。相反，我们将使用过表达miR-128的小鼠，以确定miR-128是否足以使CD 4 T细胞分化偏斜并增加发展成CD 4 T细胞的风险。 CNS自身免疫。本研究将验证以下假设：初始CD 4 + T细胞中的miRNA失调是一种潜在的免疫缺陷。 CNS自身免疫中的危险因素，可用于治疗靶向以使效应和调节性CD 4 T细胞正常化功能如果我们的假设是正确的，那么基于miRNA的治疗不仅可以预防易感人群的CNS自身免疫，个体，但改善MS患者的自身反应性T细胞。