Regulation of B cell differentiation by eIF4E

eIF4E 对 B 细胞分化的调节

• 批准号: 9244731
• 负责人: DAVID Alexander FRUMAN
• 金额: $ 18.37万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-16 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9244731
• 关键词: 5' Untranslated Regions; Address; Allergic; Alpha Cell; Antibodies; Antibody Response; Antigens; Arthritis; Autoantibodies; Autoimmune Process; B Cell Proliferation; B cell differentiation; B-Lymphocytes; Binding; Binding Proteins; Candidate Disease Gene; Cell Differentiation process; Cell division; Cells; Chemicals; Clinical; Complex; Cyclic AMP-Dependent Protein Kinases; Data; Dependence; Development; Disease; EIF4EBP1 gene; Eukaryotic Initiation Factor-4E; FRAP1 gene; Family; Generations; Genetic; Genetic Transcription; Genetic Translation; Genomics; Goals; Growth; Host Defense; IGFBP2 gene; Immune response; Immunize; Immunoglobulin Class Switching; Immunoglobulin Switch Recombination; Immunosuppression; Immunosuppressive Agents; In Vitro; Individual; Knock-out; Knowledge; Lead; Left; Light; Lupus; Lymphocyte; Malignant Neoplasms; Measurement; Measures; Messenger RNA; Mus; Pathogenicity; Pathologic; Patients; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Phosphotransferases; Process; Protein Biosynthesis; Protein Isoforms; Proteome; Raptors; Regulation; Reporting; Research; Role; Signal Pathway; Signal Transduction; Sirolimus; Structure of germinal center of lymph node; System; Technology; Testing; Therapeutic; Time; Transcriptional Regulation; Transgenic Organisms; Translating; Translational Regulation; Translations; Work; cell type; differentiated B cell; enzyme activity; epigenetic regulation; genome-wide; in vitro Model; in vivo; inducible gene expression; inhibitor/antagonist; innovation; insight; knock-down; mRNA capping; mouse model; mutant; new therapeutic target; novel; novel strategies; overexpression; programs; public health relevance; response; ribosome profiling; tool; translation factor; tumorigenesis

 DESCRIPTION (provided by applicant): The mammalian target of rapamycin (mTOR) drives lymphocyte growth, division, and differentiation following antigen stimulation. mTOR is a protein kinase that functions in two complexes, mTORC1 and mTORC2. Rapamycin is an allosteric mTORC1 inhibitor that profoundly suppresses B cell proliferation and differentiation. Conversely, elevated mTORC1 activity is seen in lymphocytes from patients with autoantibody-driven disorders including arthritis and lupus. However, the mechanisms by which mTORC1 signaling promotes B cell differentiation remain poorly defined. We have reported that genetic or pharmacological inhibition of mTORC1 suppresses antibody class switching in activated B cells. Subsequently we identified novel roles for eukaryotic initiation factor 4E (eIF4E), a downstream mTORC1 effector, in promoting B cell proliferation and antibody class switching. eIF4E regulates the translation of subsets of mRNAs in a cell type-specific manner, and is opposed by eIF4E-binding proteins (4E-BPs) that are direct substrates of mTORC1. Using novel chemical tools and genetic mouse models we have determined that the roles of mTORC1, 4E-BPs and eIF4E in class switching can be separated from their roles in proliferation. The general goal of this proposal is to define the mechanisms by which mTORC1 and eIF4E promote antibody class switching. The first Aim is to test the hypothesis that efficient class switching requires eIF4E an is opposed by 4E-BPs. We will measure isotype switching in activated B cells from mice with increased or decreased expression of eIF4E or 4E-BPs, in the presence or absence of RAP. Novel compounds that inhibit mTORC1 through an ATP-competitive manner will also be used. The role of the 4E-BP/eIF4E signaling axis will also be tested in vivo by measuring antibody responses and germinal center formation in immunized mice. The second Aim will define the mechanisms by which eIF4E regulates translation of mRNAs involved in B cell differentiation. Increasing evidence indicates that translation efficiency varies widely among individual mRNAs, and that regulated translation modulates the proteome to a similar degree as transcriptional and epigenetic regulation. In accord, genome-wide translatome studies have uncovered novel regulatory mechanisms in tumorigenesis and other processes. We will use ribosome profiling for global, unbiased identification of eIF4E targets that are differentially translated in activated B cells undergoing antibody class switching. This project is significant because a greater understanding of the translatome controlled by eIF4E and suppressed by mTORC1 inhibition might reveal novel strategies for suppressing pathogenic autoantibody responses, with a better therapeutic window than rapamycin. This work will also shed light on potential immunosuppressive effects of eIF4E inhibitors under development for cancer.

 描述（由申请方提供）：哺乳动物雷帕霉素靶标（mTOR）在抗原刺激后驱动淋巴细胞生长、分裂和分化。mTOR是一种蛋白激酶，在两种复合物中发挥作用，mTORC 1和mTORC 2。雷帕霉素是一种变构mTORC 1抑制剂，可显著抑制B细胞增殖和分化。相反，mTORC 1活性升高见于自身抗体驱动的疾病（包括关节炎和狼疮）患者的淋巴细胞。然而，mTORC 1信号转导促进B细胞分化的机制仍然不清楚。我们已经报道了mTORC 1的遗传或药理学抑制抑制活化的B细胞中的抗体类别转换。随后，我们确定了真核起始因子4 E（eIF 4 E），一种下游mTORC 1效应子，在促进B细胞增殖和抗体类别转换中的新作用。eIF 4 E以细胞类型特异性方式调节mRNA亚群的翻译，并与作为mTORC 1直接底物的eIF 4 E结合蛋白（4 E-BP）相反。使用新的化学工具和遗传小鼠模型，我们已经确定mTORC 1，4 E-BP和eIF 4 E在类别转换中的作用可以与它们在增殖中的作用分开。该提案的总体目标是定义mTORC 1和eIF 4 E促进抗体类别转换的机制。第一个目的是测试有效的类别切换需要eIF 4 E并且被4 E-BP反对的假设。我们将测量在存在或不存在RAP的情况下，来自eIF 4 E或4 E-BP表达增加或减少的小鼠的活化B细胞中的同种型转换。还将使用通过ATP竞争性方式抑制mTORC 1的新型化合物。4 E-BP/eIF 4 E信号传导轴的作用也将通过测量免疫小鼠中的抗体应答和生发中心形成来体内测试。第二个目标将定义eIF 4 E调节参与B细胞分化的mRNA翻译的机制。越来越多的证据表明，翻译效率在个体mRNA之间差异很大，并且受调节的翻译将蛋白质组调节到与转录和表观遗传调节相似的程度。与此雅阁的是，全基因组翻译组研究揭示了肿瘤发生和其他过程中的新调控机制。我们将使用核糖体分析法对在经历抗体类别转换的活化B细胞中差异翻译的eIF 4 E靶标进行全局、无偏倚的鉴定。该项目是重要的，因为更好地了解由eIF 4 E控制的翻译组和mTORC 1抑制可能揭示抑制致病性自身抗体反应的新策略，具有比雷帕霉素更好的治疗窗口。这项工作还将揭示正在开发的eIF 4 E抑制剂对癌症的潜在免疫抑制作用。