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Very early plasma cell differentiation

浆细胞极早期分化

基本信息

批准号：
10393586
负责人：
YAIR ARGON
金额：
$ 56.22万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-25 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10393586
关键词：
Adopted Adoption Affect Antibodies B Cell Proliferation B cell differentiation B-Cell Activation B-Lymphocytes Biochemical Pathway CDC2 gene Cell Cycle Cell division Cell physiology Cyclin-Dependent Kinase Inhibitor Development Endoplasmic Reticulum Degradation Pathway Event Gene Chips Gene Deletion Gene Expression Generations Genes Genetic Transcription Immune response Kinetics Messenger RNA Mitosis Modeling Molecular Chaperones Organelles Pathway interactions Pattern Phosphotransferases Plasma Cells Process Protein Secretion Proteins Proteome Proteomics Raptors Rest Role Signal Transduction Structure System TSC1 gene Testing Transcript XBP1 gene activating transcription factor adaptive immunity gene function in vivo inhibitor mRNA Expression novel plasma cell differentiation predictive modeling protein expression response transcription factor transcriptome sequencing

项目摘要

Abstract The biochemical pathways through which activated B cells initiate antibody synthesis and secretion while simultaneously undergoing cell division are unknown. Current models predict that early plasma cells generate the organelle structures needed for robust antibody secretion by activating the unfolded protein response (UPR) in response to increased antibody synthesis and through a mitosis-dependent process. This project centers on an alternative model where activated B cells prepare for plasma cell function by enacting the UPR well before increased antibody synthesis and independently of mitosis. Hence we propose that induction of the UPR in B cells is as much proactive as it is reactive. We will test this new model while also dissecting the past observations that marginal zone B cells generate plasma cells much faster than most B cells. We propose three specific aims: 1) Define biochemical pathways coordinating very early PC differentiation, 2) Define the role of constitutive mTORC1 signaling in MZ B cell differentiation, and 3) Uncouple mitosis and early PC differentiation.

抽象的活化 B 细胞启动抗体合成的生化途径同时进行细胞分裂时的分泌和分泌尚不清楚。当前的模型预测早期浆细胞产生所需的细胞器结构通过激活未折叠蛋白反应 (UPR) 来增强抗体分泌增加抗体合成并通过有丝分裂依赖性过程。这个项目以另一种模型为中心，其中激活的 B 细胞为浆细胞功能做好准备通过在增加抗体合成之前制定 UPR 且独立于有丝分裂。因此，我们认为 B 细胞中 UPR 的诱导与它一样具有主动性。是反应性的。我们将测试这个新模型，同时剖析过去的观察结果边缘区 B 细胞生成浆细胞的速度比大多数 B 细胞快得多。我们建议三个具体目标：1) 定义协调早期 PC 的生化途径分化，2) 定义组成型 mTORC1 信号在 MZ B 细胞中的作用分化，以及 3) 解开有丝分裂和早期 PC 分化。