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Regulation of B cell differentiation by eIF4E

eIF4E 对 B 细胞分化的调节

基本信息

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
项目类别：
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&apos 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

项目摘要

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.