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Functional Analysis of MicroRNAs and Target Genes in Immune Tolerance

MicroRNA 和免疫耐受靶基因的功能分析

基本信息

批准号：
10159204
负责人：
DAVID NEMAZEE
金额：
$ 64.94万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-05 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10159204
关键词：
Ablation Anabolism Animals Autoimmune Diseases Autoimmunity B-Lymphocytes Biodiversity Biological Process Bone Marrow Chemicals Code Communication Defect Development Disease Dissection Enzymes Failure GADD45A gene Genes Genetic Glycolipids Graft Rejection Grant Hematopoietic System Immune Tolerance Immune system Immunology In Vitro Inbred MRL lpr Mice Knockout Mice Lymphocyte MicroRNAs Modeling Molecular Molecular Analysis Mouse Strains Mutant Strains Mice Nature Pathway interactions Patients Peripheral Play Process Proteins Research Role Therapeutic Transgenic Organisms Untranslated RNA autoreactive B cell cancer immunotherapy central tolerance design diagnostic biomarker immunoregulation in vivo inhibitor/antagonist lupus-like mouse model novel novel therapeutic intervention peripheral tolerance plasma cell differentiation prevent systemic autoimmunity therapeutic target

项目摘要

Project Summary Autoreactive B cells play critical roles in many autoimmune diseases. Multiple immune tolerance checkpoints exist to remove autoreactive B cells or keep them under control. Defects in these checkpoints constitute the basis for the development of autoimmune diseases. Despite intensive study, our understanding of these checkpoints remains incomplete and fragmentary. MicroRNAs (miRNAs) are a new class of small non-coding RNAs that regulate a large diversity of biological processes. Hundreds of miRNAs are expressed in the immune system. While some miRNAs have been shown to play important roles in lymphocyte development and function, the roles of miRNAs in controlling immune tolerance remain poorly understood. We performed in vivo functional analysis of hundreds of miRNAs in the recently established IgMb-macroself mouse model and identified miR-148a as an important regulator of B cell central tolerance and autoimmunity (Nature Immunology 17:433-40, 2016). Further molecular analysis identified 119 target genes regulated by miR-148a in immature B cells. We examined 4 of these target genes and demonstrated that 3 of them, Gadd45a, Bim and Pten, regulate B cell central tolerance. In this proposal, we will 1) further investigate the cellular and molecular mechanisms underlying miR-148a regulation of immune tolerance and autoimmunity, focusing on its role in controlling various B cell tolerance checkpoints and plasma cell differentiation; 2) evaluate the possibility of treating systemic autoimmunity through miR-148a ablation and inhibition by genetic and chemical approaches, respectively, and 3) perform an in vitro functional screen of the other 115 miR-148a target genes to identify novel regulators of B cell tolerance. Our pilot screen has identified B4galt5 as a positive hit. As B4galt5 is a major enzyme in the glycolipid biosynthesis pathway, we speculate that this pathway plays important roles in immune tolerance. Therefore, we will elucidate the function and mechanism of B4galt5 and the glycolipid biosynthesis pathway in controlling B cell tolerance and autoimmunity.

项目总结