Plasma Cell Priming

浆细胞启动

• 批准号: 9403332
• 负责人: David M Allman
• 金额: $ 24.15万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9403332
• 关键词: Address; Antibodies; Apoptotic; Autoantibodies; Autoimmune Diseases; Autoimmunity; Automobile Driving; B cell differentiation; B-Lymphocytes; BCL1 Oncogene; Bacteria; Biochemical; Biochemical Pathway; Biological Markers; Blood; Cell Count; Cell division; Cells; Couples; Cues; Data; Ensure; Evaluation; Event; FRAP1 gene; Family; Gene Deletion; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Generations; Genes; Goals; Host Defense; Immunity; In Situ; Kinetics; Knowledge; Lupus; Mediating; Mitosis; Molecular; Pathogenicity; Phase; Phosphotransferases; Plasma Cells; Play; Population; Positioning Attribute; Process; Proteins; Receptor Signaling; Rest; Role; Signal Pathway; Signal Transduction; Sinus; Spleen; TSC1 gene; Testing; Therapeutic; Transcript; Transgenes; Translating; Translations; Up-Regulation; Work; XBP1 gene; adenoviral-mediated; combat; cytokine; differentiated B cell; experimental study; extracellular; in vitro Model; in vivo; insight; mTOR inhibition; novel strategies; plasma cell differentiation; programs; receptor; receptor expression; response; transcription factor; transcriptome sequencing

Project summary The cellular and molecular events underlying the generation of self-reactive antibodies in autoimmunity remain poorly understood. Notably, marginal zone (MZ) B cells are enriched for self-reactive B cells, and are known to generate antibody-secreting plasma cells exceptionally quickly compared to other B cells. This R21 project centers on understanding the molecular mechanisms through which MZ B cells generate plasma cells with accelerated kinetics, with a focus on defining extracellular cues and associated intracellular signaling pathways that prime MZ B cells for differentiation. The central hypothesis guiding this work is that the mTOR/mTORC1 kinase, an emerging biomarker in lupus and related autoimmune diseases, couples BAFF-receptor signaling and expression of relevant plasma cell genes to facilitate rapid induction of antibody synthesis. To test this hypothesis we will: 1) Define the role of mTOR/mTORC1 signaling in plasma cell priming, and 2) Explore the identity of extracellular inputs driving plasma cell priming in situ. These studies will enhance knowledge of the processes underlying the generation of all plasma cells including those secreting pathogenic self-reactive antibodies.

项目概要 自身反应性抗体产生的细胞和分子事件 自身免疫仍然知之甚少。值得注意的是，边缘区 (MZ) B 细胞 富含自身反应性 B 细胞，已知可产生抗体分泌血浆 与其他 B 细胞相比，细胞的生长速度异常快。这个 R21 项目的重点是 了解 MZ B 细胞产生血浆的分子机制 具有加速动力学的细胞，重点是定义细胞外线索和相关的 启动 MZ B 细胞分化的细胞内信号通路。中央 指导这项工作的假设是 mTOR/mTORC1 激酶，一种新兴的生物标志物 在狼疮和相关自身免疫性疾病中，BAFF 受体信号传导与 相关浆细胞基因的表达以促进抗体的快速诱导 合成。为了检验这一假设，我们将： 1) 定义 mTOR/mTORC1 信号传导的作用 浆细胞启动，以及 2) 探索驱动血浆的细胞外输入的身份 细胞原位引发。这些研究将增强对潜在过程的了解 所有浆细胞的产生，包括那些分泌致病性自身反应的浆细胞 抗体。