Transcriptional regulation of inflammatory and autoimmune responses

炎症和自身免疫反应的转录调节

• 批准号: 10926312
• 负责人: Vanja Lazarevic
• 金额: $ 133.4万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10926312
• 关键词: Autoimmune Diseases; Autoimmune Responses; Autoimmunity; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Cessation of life; Clinical; Combined Modality Therapy; Cytokine Receptors; Development; Disease; FOXP3 gene; Family; Future; Gene Expression Profiling; Genes; Genetic Transcription; Goals; IL17 gene; Immune; Infection; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Mediating; Multiple Sclerosis; Mus; Organ; Pathogenesis; Pathogenicity; Pathway interactions; Peripheral; Pharmaceutical Preparations; Psoriasis; Resolution; Rheumatoid Arthritis; Role; T-Lymphocyte; Testing; Therapeutic; Transcriptional Regulation; Treatment Efficacy; cytokine; genetic signature; immunoregulation; improved; novel; overexpression; pharmacologic; premature; programs; transcription factor

TH17 cells have been implicated in the pathogenesis of most common autoimmune and inflammatory diseases. However, not all TH17 cells are pathogenic. The goal of this project is to identify novel transcriptional regulators that regulate differentiation of TH17 cells with immunoregulatory versus pathogenic effector functions. We have focused on the role of Egr family of transcription factors in TH17 differentiation because high resolution transcriptional profiling predicted that Egr1 and Egr2 could function as positive regulators of TH17 differentiation program. Our studies have shown that the transcription factor Egr2, but not Egr1, is a positive regulator of TH17 cell differentiation. Egr2 augmented the expression of the TH17 lineage-signature genes: Rorc, Il17a, Il17f and Il22. Interestingly, over-expression of Egr2 in non-pathogenic TH17 cells induced the expression of pathogenicity-associated genes (e.g. Il22, Tbx21, Ccl3) and augmented the expression of immunoregulatory genes (e.g. Foxp3, Il9, Il10). To determine whether Egr2 was required for the development of immunoregulatory or pathogenic TH17 cells, we have generated mice with peripheral T cell-specific deletion of Egr2 (Egr2f/f hCD2-Cre+). In our future studies, we investigate the effects of T cell-specific Egr2-deficiency on the differentiation and effector function CD4+ T cells in the context of infections and autoimmunity.

Th17细胞与最常见的自身免疫性和炎症性疾病的发病机理有关。但是，并非所有TH17细胞都是致病性的。该项目的目的是确定具有免疫调节性与致病效应子功能的TH17细胞分化的新型转录调节剂。我们专注于EGR转录因子在Th17分化中的作用，因为高分辨率转录分析预测EGR1和EGR2可以充当TH17分化程序的积极调节剂。我们的研究表明，转录因子EGR2（而不是EGR1）是Th17细胞分化的阳性调节剂。 EGR2增强了Th17谱系签名基因的表达：RORC，IL17A，IL17F和IL22。有趣的是，非致病性TH17细胞中EGR2的过表达诱导致病性相关基因的表达（例如IL22，TBX21，CCL3），并增强了免疫调节基因的表达（例如Foxp3，IL9，IL9，IL10）。为了确定是否需要EGR2进行免疫调节或致病性TH17细胞的发展，我们已经产生了用EGR2（EGR2F/F/F HCD2-CRE+）的外周T细胞特异性缺失的小鼠。在未来的研究中，我们研究了在感染和自身免疫性的情况下，T细胞特异性EGR2缺陷对分化和效应函数CD4+ T细胞的影响。

项目成果

Regulation of myelin structure and conduction velocity by perinodal astrocytes.

• DOI: 10.1073/pnas.1811013115
• 发表时间: 2018-11-13
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Dutta DJ;Woo DH;Lee PR;Pajevic S;Bukalo O;Huffman WC;Wake H;Basser PJ;SheikhBahaei S;Lazarevic V;Smith JC;Fields RD
• 通讯作者: Fields RD