GLUCOSE AND AMINO ACID CATABOLISM IN PLASMA CELL BIOLOGY

代谢途径的使用是定制的，以满足特定细胞类型的特定功能和需求。特别感兴趣的是代谢如何支持长寿细胞的存活和抗体分泌，长寿细胞是负责体液免疫的主要细胞类型。使用浆细胞作为模型系统，我们将定义葡萄糖和氨基酸摄取如何支持这些抗体分泌细胞的长期持久性。在初步数据中，我们证明了长寿的浆细胞比短命的浆细胞输入更多的葡萄糖。葡萄糖主要用于使抗体糖基化，但一部分葡萄糖可用于糖酵解，并将所得丙酮酸导入线粒体。短寿命的浆细胞没有这种能力。我们建议定义丙酮酸的代谢命运，并解释为什么这一途径是重要的长寿的浆细胞。我们还建议定义长寿的浆细胞如何平衡增强的抗体产生与营养摄取和ER应激。最后，我们试图定义的生理信号，促进接种后的浆细胞代谢程序。该申请着重强调新的遗传和体内方法来定义，报告和功能测试体液免疫关键细胞类型中的关键代谢途径。

The usage of metabolic pathways is tailored to meet the specific functions and demands of a given cell type. Of particular interest is how metabolism supports the survival and antibody secretion of long-lived cells, the primary cell type that is responsible for humoral immunity. Using plasma cells as a model system, we will define how glucose and amino acid uptake supports long-term persistence of these antibody-secreting cells. In preliminary data, we demonstrate that long-lived plasma cells import far more glucose than do their short-lived counterparts. Glucose is primarily used to glycosylate antibodies, but a portion of this glucose can be used for glycolysis, and the resultant pyruvate imported into the mitochondria. Short-lived plasma cells do not have this capacity. We propose to define the metabolic fates of pyruvate and explain why this pathway is important in long-lived plasma cells. We also propose to define how long-lived plasma cells balance enhanced antibody production with nutrient uptake and ER stress. Finally, we seek to define the physiological signals that promote plasma cell metabolic programs following vaccination. The application heavily emphasizes new genetic and in vivo approaches to define, report, and functionally test critical metabolic pathways in a cell type critical for humoral immunity.