Control of plasma cell longevity by the IRE1 pathway

IRE1 途径控制浆细胞寿命

基本信息

批准号：
8976594
负责人：
YAIR ARGON
金额：
$ 20.18万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8976594
关键词：
Ablation Address Alleles Allografting Antibodies Antibody Response Antigens Apoptosis Apoptotic Attenuated Autoantibodies Autoantigens Autoimmune Diseases Autoimmunity B-Cell Activation B-Lymphocytes Biochemical Biochemical Pathway Bone Marrow Cell Death Cell Line Cell Survival Cells Cellular Structures Cessation of life Chronic Complement Data Endoplasmic Reticulum Endoribonucleases Event Flow Cytometry Frequencies Generations Genes Genetic Transcription Graft Rejection Health Host Defense Immunization Induced Mutation JNK-activating protein kinase Knowledge Life Longevity LoxP-flanked allele Measures Mediator of activation protein Memory B-Lymphocyte Messenger RNA Molecular Mus Mutation Pathway interactions Peripheral Plasma Cells Play Population Process Proteins Protocols documentation Regulation Reporter Role Secretory Cell Series Signal Transduction Stress System Tamoxifen Testing in vivo insight novel novel strategies null mutation overexpression plasma cell differentiation protein misfolding recombinase-mediated cassette exchange response sensor targeted treatment transcription factor

项目摘要

DESCRIPTION (provided by applicant): Long-lived antibody-secreting plasma cells (PCs) are key to host defense, but PCs secreting self-reactive antibodies can cause a spectrum of autoimmune diseases. Likewise, PCs secreting allograft-specific antibodies are major mediators of chronic graft rejection. Current B cell ablation therapies target naive and memory B cells, but spare long-lived pathogenic PCs. We propose to define the role of the unfolded protein response (UPR) in the survival and function of long-lived PCs. Although the UPR is known to control the function of professional secretory cells such as PCs, how the UPR is regulated in PCs, and its role in long-term PC survival, has not been addressed. These studies will focus on the regulation of PC survival by the UPR component and endoplasmic reticulum sensor IRE1 and a novel IRE1 regulator - PDIA6. The main hypothesis to be tested is that sustained but limited IRE1 activity is required for the survival of long-lived PCs. To test this hypothesis we wil: 1) Define the role of IRE1 activity in short- and long-lived PCs, and 2) Define the role of PDIA6 activity in short- and long-lived PCs. These studies will enhance knowledge of the processes underlying the generation of long-lived PCs, and perhaps provide insights into novel strategies to constrain the survival or activity of pathogenic PCs.

描述（由申请人提供）：长寿抗体分泌浆细胞（PC）是宿主防御的关键，但是分泌自反应性抗体的PC会引起各种自身免疫性疾病。同样，分泌同种异体特异性抗体的PC是慢性移植排斥反应的主要介体。当前的B细胞消融疗法靶向幼稚和记忆B细胞，但含有长期寿命的病原PC。我们建议定义展开的蛋白质反应（UPR）在长寿命PC的生存和功能中的作用。尽管已知UPR可以控制PCS等专业分泌细胞的功能，但在PC中如何调节UPR及其在长期PC存活中的作用尚未得到解决。这些研究将集中于UPR成分和内质网传感器IRE1和新型IRE1调节剂-PDIA6对PC生存的调节。要测试的主要假设是，长期PC的存活需要持续但有限的IRE1活性。为了检验这一假设：1）定义IRE1活性在短寿命和长期PC中的作用，以及2）定义PDIA6活性在短寿命和长寿命PC中的作用。这些研究将增强对长期PC生成的过程的知识，并可能提供有关限制病原PC生存或活性的新型策略的见解。