Control of plasma cell longevity by the IRE1 pathway

IRE1 途径控制浆细胞寿命

• 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
• 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

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）：长寿命的分泌抗体的浆细胞（PC）是宿主防御的关键，但分泌自身反应抗体的PC可引起一系列自身免疫性疾病。同样，分泌同种异体移植物特异性抗体的PC是慢性移植物排斥反应的主要介质。目前的B细胞消融疗法靶向幼稚和记忆B细胞，但不影响长寿命的致病PC。我们建议定义未折叠蛋白反应（UPR）在长寿PC的生存和功能中的作用。虽然已知UPR控制专业分泌细胞如PC的功能，但UPR如何在PC中调节，以及其在PC长期存活中的作用尚未得到解决。这些研究将集中在通过UPR组分和内质网传感器IRE1以及新型IRE1调节剂PDIA6来调节PC存活。待检验的主要假设是，长寿命PC的存活需要持续但有限的IRE1活性。为了检验这一假设，我们将：1）定义IRE1活性在短寿命和长寿命PC中的作用，和2）定义PDIA 6活性在短寿命和长寿命PC中的作用。这些研究将增强对长寿命PC生成过程的了解，并可能为限制致病PC的生存或活动的新策略提供见解。