Cyclic AMP-mediated apoptosis in lymphoid malignancies

淋巴恶性肿瘤中环磷酸腺苷介导的细胞凋亡

• 批准号: 7420912
• 负责人: ADAM LERNER
• 金额: $ 24.12万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7420912
• 关键词: 8-((4-chlorophenyl)thio)cyclic-3' ,5' -AMP; 8-cyclopentyl-1,3-dimethylxanthine; Accounting; Adenylate Cyclase; Adhesions; Apoptosis; Apoptotic; B Cell Proliferation; B-Lymphocytes; BAD gene; Bad protein; CXC Chemokines; Catalytic Domain; Cells; Cessation of life; Chronic; Chronic Lymphocytic Leukemia; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic Nucleotides; Disease; Diterpenes; Family member; Forskolin; Functional disorder; Glycosaminoglycans; Guanine Nucleotide Exchange Factors; Hematopoietic; Human; Hyaluronan; IL8 gene; Leukemic Cell; Lymphoblastic Leukemia; Malignant lymphoid neoplasm; Mediating; Mitochondria; Mitochondrial Carnitine Palmitoyltransferase Pathway; Nucleotides; Pathway interactions; Patients; Peripheral; Phosphoric Monoester Hydrolases; Play; Principal Investigator; Protein Dephosphorylation; Protein Phosphatase 2A Regulatory Subunit PR53; Proteins; Reporting; Resistance; Role; Rolipram; Signal Pathway; Signal Transduction; T-Lymphocyte; Testing; Transcript; Transcriptional Activation; Treatment Efficacy; United States Environmental Protection Agency; Up-Regulation; adult leukemia; analog; autocrine; chemokine; chemotherapy; chronic T-cell leukemia; inhibitor/antagonist; migration; novel; phosphoric diester hydrolase; programs; therapeutic target; tool

DESCRIPTION (provided by applicant): Inhibitors of type 4 cAMP phosphodiesterase (PDE4) such as rolipram-induced apoptosis in B cell chronic lymphocytic leukemia, even in the absence of exogenous pharmacologic agents that activate adenylate cyclase such as the diterpene forskolin. T cells or T-CLL, in contrast, are resistant to rolipram-induced apoptosis. Rolipram induces a mitochondrial death pathway in B-CLL cells, perhaps in part due to activation of the phosphatase PP2A and dephosphorylation of BAD. Remarkably, cAMP can also activate an antiapoptotic pathway in B-CLL through EPAC1, a cAMP-activated Rap1 GDP exchange factor. B-CLL cells are unique among circulating hematopoietic cells in their functional expression of EPAC1, suggesting EPAC1 signaling may play a role in the pathophysiology of this disease. Specific Aim I. To elucidate the mechanism by which PDE4 inhibitors activate a mitochondrial pathway of apoptosis in B-CLL, we will: A) Determine whether PDE4 inhibitor-induced apoptosis in CLL is PKA-mediated. B) Determine whether rolipram-induced apoptosis in CLL is EPAC-independent. C) Determine the mechanism for rolipram-induced augmented CLL PP2A activity. D) Determine whether PP2A is required for rolipram-mediated apoptosis in CLL. Specific Aim II. To contrast the roles of EPAC and PKA signaling in CLL, we will: A) Determine whether PKA activation by PDE4 inhibitors blocks the ability of EPAC activation to augment B-CLL chemokine transcript levels. B) Determine if EPAC-induced augmentation of chemokine and/or Mcl-1 transcripts is unique to B-CLL among circulating hematopoietic cells. C) Determine if EPAC-induced augmentation of B-CLL survival results from up-regulation of an IL-8 autocrine loop. D) Determine whether PKA and EPAC differentially regulate PI3K or its downstream targets. Specific Aim III. To determine whether the unique expression of functional EPAC in CLL cells is of pathophysiologic importance, we will: A) Examine the effects of EPAC activation on CLL adhesion and migration. B) Compare the effects of EPAC and PKA activation on both basal and chemotherapy-induced CLL survival. C) Compare the effects of EPAC and PKA on CLL and B cell proliferation.

描述（由申请人提供）：4型营CAMP磷酸二酯酶（PDE4）的抑制剂，例如Rolipram诱导的B细胞慢性淋巴细胞性白血病中的Rolipram诱导的凋亡，即使没有外源性药物学剂，这些药物没有激活腺苷酸化酶的外源性药物学剂，例如丁乙烯酸酯循环素。相比之下，T细胞或T-CLL对Rolipram诱导的凋亡具有抗性。 Rolipram诱导B-CLL细胞中的线粒体死亡途径，部分原因是磷酸酶PP2A的激活和不良磷酸化。值得注意的是，CAMP还可以通过CAMP激活的RAP1 GDP交换因子EPAC1激活B-CLL中的抗凋亡途径。 B-CLL细胞在循环造血细胞中在其EPAC1的功能表达中是独一无二的，这表明EPAC1信号传导可能在该疾病的病理生理学中起作用。具体目的I.为了阐明PDE4抑制剂激活B-CLL中凋亡的线粒体途径的机制，我们将：a）确定PDE4抑制剂诱导的CLL中PKA介导的pDE4抑制剂是否介导了PKA介导。 b）确定rolipram诱导的CLL中凋亡是否与EPAC无关。 c）确定Rolipram诱导的增强CLL PP2A活性的机制。 d）确定Rolipram介导的CLL凋亡是否需要PP2A。具体目标II。为了对比EPAC和PKA信号在CLL中的作用，我们将：a）确定PDE4抑制剂的PKA激活是否会阻止EPAC激活增加B-CLL趋化因子转录物水平的能力。 b）确定EPAC诱导的趋化因子和/或MCL-1转录物的增强是否在循环造血细胞中是B-CLL所独有的。 c）确定EPAC诱导的B-CLL存活的增强是否是由IL-8自分泌环上的上调引起的。 d）确定PKA和EPAC是否差异调节PI3K或其下游靶标。特定目标III。为了确定功能EPAC在CLL细胞中的独特表达是否具有病理生理的重要性，我们将：a）检查EPAC激活对CLL粘附和迁移的影响。 b）比较EPAC和PKA激活对基底和化学疗法诱导的CLL存活的影响。 c）比较EPAC和PKA对CLL和B细胞增殖的影响。