Glucose and Amino Acid Catabolism in Plasma Cell Biology

浆细胞生物学中的葡萄糖和氨基酸分解代谢

基本信息

批准号：
10464277
负责人：
Deepta Bhattacharya
金额：
$ 60.34万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-13 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10464277
关键词：
Ablation Amino Acid Transporter Amino Acids Antibodies Antibody Formation Antibody-mediated protection Biological Bone Marrow CRISPR screen CRISPR/Cas technology Carbon Catabolism Cell Survival Cell secretion Cells Cellular biology Chimera organism Coupled Cre driver Data Energy Metabolism Exocytosis Funding Gene Deletion Genetic Genetic Transcription Glucose Goals Humoral Immunities Immunity Immunization Immunoglobulins Infection Length Link Longevity Measures Mediator Metabolic Metabolic Pathway Metabolism Mitochondria Morphology Multiple Myeloma Nutrient Pathway interactions Physiological Plasma Cells Resistance Role Shapes Source Surface Testing Time Vaccination Vaccines Vesicle Virus Diseases Work cell type differential expression experimental study extracellular genome-wide glycosylation in vivo insight interest mass spectrometric imaging pandemic disease pathogen response stable isotope sugar tool uptake vacuolar H+-ATPase

项目摘要

Abstract: 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 plasma cells, the primary cell type that is responsible for humoral immunity. The lifespan of these cells dictates the duration of antibody-mediated immunity after infections or vaccines—a particularly relevant topic in the midst of this pandemic. During the previous funding period, our work suggested a surprisingly minimal role for transcriptional pathways in controlling plasma cell lifespan. Instead, metabolic pathways functionally distinguish plasma cells of differing lifespans. Using newly created genetic tools, we will rapidly define and dissect essential plasma cell metabolic pathways in vivo. We will use newly generated plasma cell Cre-drivers, lentiviral bone marrow chimeras, and CRISPR/Cas9 approaches to functionally define mitochondrial dynamics, essential metabolic pathways, and vesicular maturation pathways that promote plasma cell lifespan and antibody secretion. These approaches will be coupled with sensitive imaging mass spectrometry and stable isotope-tracing experiments to provide mechanistic insight. Specifically, our experiments will define the importance of mitochondrial fission and fusion in plasma cell energy metabolism, antibody production, and survival. Physiological experiments using viral infections and immunizations will define key factors that promote plasma cell metabolic re-programming as these cells become progressively longer lived. Second, based upon results of a completed genome-wide CRISPR/Cas9 screen, we will pursue the importance of V-type ATPases in amino acid uptake, plasma cell lifespan, and antibody secretion in vivo.

抽象的：定制代谢途径的使用以满足给定细胞类型的特定功能和需求。特别感兴趣的是，新陈代谢如何支持浆细胞的生存和抗体分泌，负责体液免疫的主要细胞类型。这些细胞的寿命决定了抗体介导的感染或疫苗后的免疫力 - 在此过程中特别相关的话题大流行。在上一个资金期间，我们的工作提出了令人惊讶的最小作用控制浆细胞寿命的转录途径。相反，代谢途径在功能上区分不同寿命的血浆细胞。使用新创建的遗传工具，我们将迅速定义和剖析必需的浆细胞代谢途径在体内。我们将使用新生成的等离子电池驱动器，慢病毒骨髓嵌合体和CRISPR/CAS9在功能上定义线粒体动力学的方法必需的代谢途径和囊泡成熟途径，可促进浆细胞寿命和抗体分泌。这些方法将与敏感成像质谱和稳定相结合同位素追踪实验可提供机械洞察力。具体来说，我们的实验将定义线粒体裂变和融合在浆细胞能量代谢，抗体产生和融合的重要性生存。使用病毒感染和免疫接种的生理实验将定义促进的关键因素随着这些细胞逐渐持续更长的寿命，血浆细胞代谢重新编程。第二，基于完整全基因组CRISPR/CAS9屏幕的结果，我们将追求V型ATPases的重要性在氨基酸摄取中，浆细胞寿命和体内抗体分泌。