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The Role of Myeloid Cell-Specific Ten-Eleven Translocase 2 (TET2) in Regulation of Neuroinflammation

骨髓细胞特异性 10-11 转位酶 2 (TET2) 在神经炎症调节中的作用

基本信息

批准号：
10378505
负责人：
Ashley Munie Gardner
金额：
$ 3.23万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10378505
关键词：
Address Adoptive Transfer Aggressive Clinical Course Animal Model Anti-Inflammatory Agents Antigen Presentation Autoimmune Blocking Antibodies Blood Bone Marrow CD4 Positive T Lymphocytes CD86 gene CNS autoimmune disease CNS autoimmunity Cell physiology Cells Cellular Infiltration ChIP-seq Clinical Cytokine Activation Cytosine DNA Data Demyelinations Development Dioxygenases Disease Down-Regulation Enterobacteria phage P1 Cre recombinase Enzymes Epigenetic Process Etiology Experimental Autoimmune Encephalomyelitis Family Flow Cytometry Fluorescence-Activated Cell Sorting Frequencies Gene Expression Genetic Genetic Predisposition to Disease Genetic Transcription Goals Immunohistochemistry In Vitro Inflammation Inflammatory Interleukin-1 beta Interleukin-4 Interleukin-6 Knock-out Laboratories Lead Malignant Neoplasms Measures Mediating Methylation Microarray Analysis Modification Multiple Sclerosis Multiple Sclerosis Lesions Mus Myelin Myelogenous Myeloid Cell Activation Myeloid Cells Nervous System Trauma Neuraxis Nucleic Acid Regulatory Sequences Outcome PTPRC gene Pathogenesis Pathologic Pathology Pathway interactions Patients Peripheral Blood Mononuclear Cell Phagocytosis Phenotype Play Population Production Property Regulation Reporter Research Role Severities Spleen Susceptibility Gene System Tamoxifen Time Transcript Transgenic Mice alpha ketoglutarate central nervous system demyelinating disorder chemokine conditional knockout cytokine demethylation disability experience genetic risk factor interest loss of function mutation member mouse model multiple sclerosis patient multiple sclerosis treatment neuroimmunology neuroinflammation neuropathology neurotoxicity new therapeutic target novel oxidation programmed cell death ligand 1 promoter single-cell RNA sequencing therapeutic target translocase

项目摘要

PROJECT SUMMARY Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) believed to be autoimmune in etiology. Analysis of MS lesions, as well as studies in experimental autoimmune encephalomyelitis (EAE), a murine model of MS, have indicated that myeloid cells are likely a critical component of the pathogenesis of CNS autoimmunity. Recently, Ten-Eleven Translocase 2 (TET2) was identified as a genetic susceptibility locus for MS. TET2 is a Fe(III)-, α-ketoglutarate-dependent enzyme that catalyzes the oxidation of methylated cytosine to 5’-hydroxymethyl cytosine (5hmC) and promotes active demethylation. 5hmC is a stable epigenetic mark that can either activate or repress gene expression in a cell- and loci-dependent manner. There is growing evidence that TET2 acts as a negative regulator of myeloid cell activation and function, promoting a homeostatic or anti-inflammatory cell state. My hypothesis is that TET2 restrains the pro- inflammatory functions of myeloid cells to limit inflammation, neurological damage, and disability during CNS autoimmunity. Supporting this hypothesis, TET2 and 5hmC were found to be reduced in peripheral blood mononuclear cells of MS patients when compared with controls. Preliminary data from our laboratory demonstrates that the reduction of TET2 and 5hmC in peripheral blood mononuclear cells is recapitulated in EAE, and that TET2 transcripts and 5hmC content are further reduced in CNS-infiltrating myeloid cells compared with the periphery. Additionally, adoptive transfer of encephalitogenic Th17 cells into Tet2+/- mice led to an exacerbated clinical course compared with Tet2+/+ mice. To continue addressing my hypothesis, I will first examine the impact of TET2 deficiency in myeloid cells on clinical and pathological outcomes of EAE (Aim 1). I will do this by examining the EAE disease course, pathology, and cellular infiltration in mice where Tet2 is knocked out specifically in myeloid cells using a Cre/lox genetic system. Additionally, I will identify the targets of TET2 in CNS-infiltrating myeloid cells, such as the suppression of pro-inflammatory cytokine production and the conversion of myeloid cells from a pro-inflammatory phenotype to an anti-inflammatory phenotype (Aim 2). Completion of these aims will contribute to the fields of neuroimmunology and epigenetics by exploring a novel mechanism of myeloid cell regulation during CNS autoimmunity, and may lead to the discovery of novel myeloid cell-specific therapeutic targets for the treatment of MS and related disorders.

项目摘要多发性硬化（MS）是中枢神经系统（CNS）的炎性脱髓鞘疾病，是自身免疫性疾病MS病变的分析，以及实验性自身免疫性脑脊髓炎（EAE），MS的鼠模型，已经表明髓样细胞可能是关键组分中枢神经系统自身免疫的发病机制。最近，10 - 11易位酶2（TET 2）被鉴定为一种具有生物学活性的蛋白。 TET 2是一种Fe（III）-，α-酮戊二酸依赖性酶，催化MS的遗传易感性位点。甲基化胞嘧啶氧化为5 '-羟甲基胞嘧啶（5 hmC），并促进主动去甲基化。5hmC 是一种稳定的表观遗传标记，可以激活或抑制细胞和基因座依赖性的基因表达，方式越来越多的证据表明TET 2作为骨髓细胞活化和功能的负调节剂，促进体内平衡或抗炎细胞状态。我的假设是TET 2抑制了亲- 骨髓细胞的炎症功能，以限制CNS期间的炎症、神经损伤和残疾自身免疫支持这一假设，TET 2和5 hmC被发现在外周血中减少 MS患者的单核细胞与对照组相比。我们实验室的初步数据表明外周血单个核细胞中TET 2和5 hmC的减少在 EAE，TET 2转录物和5 hmC含量在CNS浸润的髓样细胞中进一步降低，与外围。此外，致脑炎性Th 17细胞过继转移到Tet 2 +/-小鼠中导致了与Tet 2 +/+小鼠相比，临床病程加重。为了继续阐述我的假设，我将首先检查髓系细胞中TET 2缺陷对EAE临床和病理结果的影响（目的1）。我将通过检查Tet 2表达的小鼠的EAE病程、病理学和细胞浸润来实现这一点。使用Cre/lox遗传系统在骨髓细胞中特异性敲除。此外，我将确定的目标， TET 2在CNS浸润性髓样细胞中的作用，如抑制促炎细胞因子的产生和骨髓细胞从促炎表型转化为抗炎表型（目的2）。这些目标的完成将有助于神经免疫学和表观遗传学领域探索一种新的中枢神经系统自身免疫过程中髓样细胞调节的机制，并可能导致发现新的髓样细胞免疫抑制剂。用于治疗MS和相关病症的细胞特异性治疗靶点。