Glucose energy metabolism in the growth and survival of B lymphocytes

B 淋巴细胞生长和存活中的葡萄糖能量代谢

• 批准号: 7843495
• 负责人: Thomas C. Chiles
• 金额: $ 39.13万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2011-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7843495
• 关键词: 1-Phosphatidylinositol 3-Kinase; 6-Phosphofructokinase; ATP Citrate (pro-S)-Lyase; Antigen Receptors; Antigens; Apoptosis; Autoantibodies; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Biochemistry; Bioenergetics; Biological; Carbon; Cholesterol; Cis-Acting Sequence; DNA biosynthesis; Data; Development; Energy Metabolism; Enzymes; Event; Excision; Fc Receptor; Gene Expression; Genetic Transcription; Glucose; Glucosephosphate Dehydrogenase; Glycolysis; Glycolysis Inhibition; Goals; Growth; Growth Factor; Growth and Development function; Housekeeping; Immune System Diseases; Immune response; Immunoglobulin G; Immunoglobulins; Link; Lymphocyte; Lymphocyte Activation; Lymphocyte Function; Lymphoma; Maintenance; Mammalian Cell; Mature B-Lymphocyte; Mediating; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Nuclear; Pathway interactions; Pentosephosphate Pathway; Phase; Play; Production; Receptor Signaling; Receptors, Antigen, B-Cell; Regulation; Role; Signal Pathway; Signal Transduction; Testing; Time; Tyrosine Phosphorylation; antigen challenge; blood glucose regulation; cell growth; crosslink; diabetic; glucose metabolism; human FCGR2B protein; information gathering; lipid biosynthesis; meetings; novel; peripheral tolerance; programs; receptor; response; therapy development; transcription factor

Lymphocytes use considerable amounts of energy to maintain survival and to support growth and effector functions in response to antigen challenge. Aberrant glucose energy metabolism can contribute to autoimmune disease and lymphomas. During the past three decades the role of the B-cell antigen receptor (BCR) in promoting B-cell growth and development has been established. It is also clear that co-receptors (e.g., IgG Fc receptor, FcRIIB) can negatively modulate both Ag-dependent and Ag-independent growth responses. An appreciation for FcRIIB in the maintenance of peripheral tolerance is highlighted by the observation that its deletion can result in autoantibody production and autoimmune disease. BCR and FcRIIB mediated control of lymphocyte function likely requires re-programming of metabolism; however, virtually nothing is known about how signal input from these receptors modulate cellular metabolism or the biological significance of such regulation. On this point, we have recently discovered that the BCR possesses the capacity to reprogram glucose metabolism in real-time to meet the changing bioenergetic and de novo macromolecular synthetic demands associated with B lymphocyte activation. This is achieved by phosphatidylinositol 3-kinase (PI-3K)-dependent signaling that targets several essential rate-limiting enzymes involved in de novo lipogenesis (via activation of ATP citrate lyase, ACL), and entry into the oxidative pentose phosphate pathway (via induction of glucose 6-phosphate dehydrogenase (G6PD) gene expression) to support B-cell growth and DNA replication, respectively. We have also uncovered a novel pathway that links FcRIIB engagement to decreased glycolysis, a response remarkably similar to decreased glycolytic flux observed upon removal of growth factors from mammalian cells that leads to initiation of apoptosis. Our results suggest that the rate-limiting glycolytic enzyme, phosphofructokinase-1 (PFK-1) is inhibited following FcRIIB engagement. The central goal of this application is to delineate the molecular regulation of glucose energy metabolism involved in B lymphocyte function and growth responses by signal input from the BCR and FcRIIB. The proposed studies will seek to test two specific aims. Aim I will elucidate the molecular regulation of ACL activation with respect to BCR-dependent signaling. Aim II will elucidate the molecular mechanisms underlying inhibition of glycolysis following FcRIIB engagement. Information gathered from this project will also help to distill how dysregulation of glucose metabolism contributes to aberrant B-cell responses and may identify metabolic targets for the development of therapies to treat certain immune diseases characterized by uncontrolled expansion of B cells.

淋巴细胞使用大量的能量来维持生存，支持生长和应答抗原攻击的效应功能。异常的葡萄糖能量代谢可导致自身免疫性疾病和淋巴瘤。在过去的三十年中，b细胞抗原受体（BCR）在促进b细胞生长和发育中的作用已经确立。同样清楚的是，共受体（例如IgG Fc受体FcRIIB）可以负向调节ag依赖性和ag非依赖性的生长反应。FcRIIB在维持外周耐受性方面的作用，通过观察其缺失可导致自身抗体产生和自身免疫性疾病而得到重视。BCR和FcRIIB介导的淋巴细胞功能控制可能需要代谢重编程；然而，关于这些受体的信号输入如何调节细胞代谢或这种调节的生物学意义，几乎一无所知。在这一点上，我们最近发现BCR具有实时重编程葡萄糖代谢的能力，以满足与B淋巴细胞激活相关的生物能量和新生大分子合成需求的变化。这是通过磷脂酰肌醇3-激酶（PI-3K）依赖的信号传导来实现的，该信号分别靶向参与从头脂肪生成的几种基本限速酶（通过激活ATP柠檬酸裂解酶，ACL）和进入氧化戊糖磷酸途径（通过诱导葡萄糖6-磷酸脱氢酶（G6PD）基因表达），以支持b细胞生长和DNA复制。我们还发现了一种新的途径，将FcRIIB参与与糖酵解减少联系起来，这种反应与从哺乳动物细胞中去除生长因子导致细胞凋亡时观察到的糖酵解通量减少非常相似。我们的研究结果表明，在FcRIIB参与后，限速糖酵解酶磷酸果糖激酶-1 （PFK-1）受到抑制。本应用程序的中心目标是通过BCR和FcRIIB的信号输入来描述参与B淋巴细胞功能和生长反应的葡萄糖能量代谢的分子调控。拟议的研究将试图测试两个具体目标。目的我将阐明ACL激活的分子调控与bcr依赖的信号。目的II将阐明FcRIIB参与后糖酵解抑制的分子机制。从这个项目中收集的信息也将有助于提炼出葡萄糖代谢失调如何导致异常的B细胞反应，并可能确定代谢靶点，以开发治疗以B细胞不受控制的扩张为特征的某些免疫疾病的疗法。

项目成果

Anti-inflammatory effects of novel barbituric acid derivatives in T lymphocytes.

新型巴比妥酸衍生物对 T 淋巴细胞的抗炎作用。

• DOI: 10.1016/j.intimp.2016.06.004
• 发表时间: 2016
• 期刊: International immunopharmacology
• 影响因子: 5.6
• 作者: Xu,Chenjia;Wyman,ArleneR;Alaamery,ManalA;Argueta,ShannonA;Ivey,FDouglas;Meyers,JohnA;Lerner,Adam;Burdo,TriciaH;Connolly,Timothy;Hoffman,CharlesS;Chiles,ThomasC
• 通讯作者: Chiles,ThomasC