Lymphocyte Survival: Implications for lymphomagenesis

淋巴细胞存活：对淋巴瘤发生的影响

基本信息

批准号：
7915831
负责人：
CRAIG B THOMPSON
金额：
$ 9.13万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7915831
关键词：
ATP Citrate (pro-S)-Lyase Aconitate Hydratase Activated Lymphocyte Address Allosteric Regulation Amino Acids Antigen Receptors Antigens Autoimmunity Bioenergetics Biological Assay CD28 gene Catabolism Cell Death Cell Line Cell Proliferation Cell Survival Cells Clinical Cytokine Receptors Dependence Dependency Development Diphosphates Disease Environment Enzymes Event Exhibits Funding Genes Glucose Glycolysis Growth Hepatocyte Human Immune response Immunosuppressive Agents In Vitro Interleukin-2 Lead Link Lipids Lymphocyte Lymphocyte Activation Lymphoma Lymphomagenesis Maintenance Mediating Mediator of activation protein Membrane Microdomains Membrane Potentials Metabolic Metabolic Pathway Metabolism Methodology Methotrexate Mitochondria Molecular Mus NADH NADP Non-Hodgkin&apos s Lymphoma Nucleotide Biosynthesis Nucleotides Nutrient Oxidation-Reduction Pathway interactions Patients Pentosephosphate Pathway Phospholipids Phosphotransferases Play Post-Translational Protein Processing Preparation Prevention therapy Principal Investigator Production Proliferating Protein Biosynthesis Proteins Pyruvate Pyruvates RNA Interference Reaction Reactive Oxygen Species Regulation Relative (related person)Research Personnel Ribose Role Shunt Device Signal Pathway Signal Transduction Source Stress T-Lymphocyte Testing Therapeutic Therapeutic Agents Therapeutic Intervention Toxic effect Up-Regulation Work addiction assay development base blood glucose regulation cell growth cell transformation cytokine design enzyme activity extracellular fatty acid oxidation gene repression glucose metabolism glucose uptake in vivo inhibitor/antagonist lipid metabolism lymphocyte proliferation meetings membrane synthesis mitochondrial membrane novel nucleotide metabolism oxidation prevent programs proto-oncogene protein pim receptor research study response sugar tumor uptake

项目摘要

DESCRIPTION (provided by applicant): Lymphocytes lack the ability to take up sufficient nutrients from the extracellular environment to maintain survival in the absence of extrinsic signals. Even quiescent lymphocytes are dependent on extracellular signals to direct the nutrient uptake necessary for viability. The inability to take up extracellular nutrients on a cell-autonomous basis also limits the ability of lymphocytes to engage in antigen receptor-induced proliferation unless the cells simultaneously receive extracellular signals that direct nutrient uptake and metabolism to sufficient levels to meet the increased bioenergetic demands of growth and proliferation. Over the last several years, we have demonstrated that one way in which costimulatory receptors, such as CD28, and cytokines, such as IL-2, contribute to cell growth is through directly stimulating antigen-activated lymphocytes to increase their uptake and metabolism of glucose and amino acids. Two independent metabolic signaling pathways have been identified in lymphocytes: the PISK/Akt and JAK/STAT/Pim pathways. These two signaling pathways have direct and partially overlapping effects on the ability of lymphocytes to take up essential nutrients and utilize these nutrients to fuel ATP production and protein, lipid, and nucleotide synthesis. Although both pathways are used during the growth and proliferation of non- transformed lymphocytes, constitutive activation of either Akt-1 or Pim-2 is sufficient to activate nutrient uptake to levels that support both cell autonomous survival and antigen receptor-induced cell growth and proliferation. In this continuation proposal, we seek to investigate the molecular basis by which T cells utilize the PISK/Akt and JAK/STAT/Pim pathways to convert exogenous glucose into the lipids and nucleotides needed for cell growth and/or proliferation. Three specific aims are envisioned: 1) Determine the role of glucose-dependent lipid production in lymphocyte growth and survival; 2) Study the role of glucose- dependent synthesis of nucleotide precursors and NADPH in the regulation of lymphocyte proliferation; and 3) Define whether inhibitors of the glucose-dependent metabolic pathways activated by the PISK/Akt or JAK/STAT/Pim pathways can selectively impair the growth of spontaneous lymphomas. A more thorough characterization of how costimulatory receptors and cytokines regulate the metabolic processes of lipid and nucleotide biosynthesis may lead to the development of novel therapies for the prevention or treatment of lymphoma.

描述（由申请人提供）：淋巴细胞缺乏从细胞外环境吸收足够营养物质以在没有外来信号的情况下维持生存的能力。即使是静止的淋巴细胞也依赖于细胞外信号来引导生存所需的营养物质的吸收。无法在细胞自主的基础上吸收细胞外营养物质也限制了淋巴细胞参与抗原受体诱导的增殖的能力，除非细胞同时接收细胞外信号，将营养物质吸收和代谢引导到足够的水平，以满足细胞增加的生物能需求。生长和增殖。在过去的几年中，我们已经证明，共刺激受体（例如 CD28）和细胞因子（例如 IL-2）促进细胞生长的一种方式是通过直接刺激抗原激活的淋巴细胞来增加其对葡萄糖的摄取和代谢和氨基酸。在淋巴细胞中已鉴定出两条独立的代谢信号传导途径：PISK/Akt 和 JAK/STAT/Pim 途径。这两条信号传导途径对淋巴细胞吸收必需营养素并利用这些营养素促进 ATP 产生以及蛋白质、脂质和核苷酸合成的能力具有直接和部分重叠的影响。尽管这两种途径都在非转化淋巴细胞的生长和增殖过程中使用，但 Akt-1 或 Pim-2 的组成型激活足以将营养吸收激活至支持细胞自主存活和抗原受体诱导的细胞生长和增殖的水平。在这个延续提案中，我们试图研究 T 细胞利用 PISK/Akt 和 JAK/STAT/Pim 途径将外源葡萄糖转化为细胞生长和/或增殖所需的脂质和核苷酸的分子基础。设想了三个具体目标：1）确定葡萄糖依赖性脂质产生在淋巴细胞生长和存活中的作用； 2）研究葡萄糖依赖性核苷酸前体合成和NADPH在调节淋巴细胞增殖中的作用； 3) 确定由 PISK/Akt 或 JAK/STAT/Pim 途径激活的葡萄糖依赖性代谢途径的抑制剂是否可以选择性损害自发性淋巴瘤的生长。对共刺激受体和细胞因子如何调节脂质和核苷酸生物合成的代谢过程的更彻底的表征可能会导致预防或治疗淋巴瘤的新疗法的开发。