Fit to remember? B cell metabolic 'fitness', AMPK & recall antibody responses

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• 批准号: 8891563
• 负责人: Mark R Boothby
• 金额: $ 39.25万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891563
• 关键词: 5' -AMP-activated protein kinase; Address; Adoptive Transfer; Affinity; Alleles; Anabolism; Antibodies; Antibody Formation; Antidiabetic Drugs; Antigens; B-Lymphocytes; Biochemical; Biological Models; Biology; CD8B1 gene; Cell Lineage; Cell Survival; Cell physiology; Cells; Characteristics; Complement; Complex; Disease; Epitopes; Equilibrium; Fostering; Generations; Glucose; Glycolysis; Health; Humoral Immunities; Hypoxia; Immune; Immune response; Immune system; In Vitro; Interleukin-4; Lead; Learning; Leukocytes; Life; Lipids; Lymphoid; Maintenance; Measures; Mediating; Memory; Memory B-Lymphocyte; Metabolic; Metabolic Pathway; Metabolism; Metformin; Microbe; Modeling; Mus; Nutrient; Outcome; Pathway interactions; Performance; Phenotype; Phosphotransferases; Physiology; Plasma Cells; Play; Population; Process; Protein Isoforms; Proteins; Reaction; Regulation; Research; Role; STAT6 gene; Signal Pathway; Signal Transduction; Site; Staging; Structure of germinal center of lymph node; Systems Development; T-Lymphocyte; Testing; Tissues; Transferase; Transgenes; Vaccines; adaptive immunity; anaerobic glycolysis; base; fatty acid oxidation; fitness; functional outcomes; gain of function; long term memory; loss of function; mTOR protein; mouse model; novel; oxidation; response; sensor; transcription factor; vaccine efficacy

DESCRIPTION (provided by applicant): Humoral memory is central to the capacity of vaccines to protect against microbes and is a key feature of adaptive immunity. A major determinant of this process is the potency with which germinal center (GC) reactions foster the differentiation and maintenance of memory B cells, which in turn are critical determinants of recall responses. Much has been learned about the potential fates of a B cell after its activation, including vital contributions of BCR affinity for Ag and other global features of GC reactions, but remarkably little is known about how signaling within the B cell impacts memory. Accumulating evidence with in vitro manipulations as well as mouse model systems provides indications of a regulatory inter-play of local physiology (e.g., nutrient supply) with signaling in cells of the immune system and their fate or functional characteristics. The unique biology of B cells and memory implies that they use novel metabolic mechanisms. However, very little is known about metabolic regulation for the B lymphoid lineage and especially not for B cell memory or the persistence of adequate concentrations of Ab. AMP-activated kinase (AMPK), the target of anti-diabetic agents such as metformin, is central to regulation of the balance between energy generation versus utilization in bio-synthesis. We have found that the predominant isoform of AMPK in B cells, AMPK�1, promoted the capacity for a recall Ab response in a B cell-intrinsic role. We also developed evidence of a pathway parallel to AMPK, on which an ADP-ribosyl transferase, PARP14, promotes increases in glycolysis, glucose oxidation, and B cell survival. Moreover recall Ab responses of several Ab isotypes depended on PARP14. These and further findings lead us to hypothesize that AMPK� promotes the generation or maintenance of Ag-specific memory B cells, and that this function is exerted at least in part through promotion of metabolic fitness [fatty acid oxidation (FAO) as well as glycolysis and glucose oxidation]. The research also will address an unresolved paradox from key studies of the central paradigm of CTL memory, in which (FAO) is associated with memory fate while glycolysis ties to effector-like phenotype. The conundrum is that the balancing act was attributed to AMPK activity, but this kinase promotes both FAO and glycolysis. We will test the hypothesis that differential regulation of these forms of energy generation is based on mTOR-regulated activity of HIF-1, a transcription factor that may directly repress FAO alongside its activation of glycolysis. To test the impact of AMPK activity on humoral recall, and elucidate a mechanism by which AMPK-driven metabolic pathways can be balanced, we have three specific Aims. The first (Aim 1) is to establish a specific B lineage- intrinsic function for the key metabolic regulator, AMPK, in memory for humoral immunity. Moreover, we plan to test a model in which HIF-1 is integrated with AMPK in setting B cell metabolic balance and recall Ab responses (Aim 2). Finally, we will evaluate if mTOR is an effector of AMPK and HIF-1 in B cells and humoral memory (Aim 3). The expected outcome of the proposed studies is that we will uncover novel roles for AMPK and HIF-1 in determining the metabolic profile in B cells and functional outcome in humoral immunity.

描述：体内记忆是保护疫苗的核心，是VE免疫的关键特征。是召回响应的关键决定因素。 包含BCR亲和力对AG和GC反应的其他全球特征的重要贡献，但 关于撞击记忆中的信号传导知之甚少。记忆的使用l代谢机制。在生物合成中，我们发现了AMPK 1的AMPK的主导者，促进了回忆AB重新恢复的作用。糖酵解，葡萄糖氧化的增加，再召回几个AB几个AB几个AB SEOTYPEND，取决于PARP14。代谢适应性（粮农组织）以及糖酵解和葡萄糖氧化。平衡行为归因于AMPK活性激酶促进粮农组织和糖酵解。 ，阐明了一种机制，通过将AMPK驱动的代谢途径可以平衡，我们有三个特定的目标（AIM 1）是建立谱系的谱系。 1与AMPK整合在设置B细胞中，并回忆AB响应（AM 2），我们将评估MTOR是否是AMPK的效应子，而在B细胞中1的效果（AIM 3）这将揭示作用的发挥作用，即使B细胞中的代谢概况提交了B细胞中的代谢曲线，并在体液mmunity中起作用。