权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
7626486
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
项目类别：
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/7626486
关键词：
8-((4-chlorophenyl)thio)cyclic-3&apos ,5&apos -AMP 8-cyclopentyl-1,3-dimethylxanthine Accounting Adenylate Cyclase Adhesions Apoptosis Apoptotic B Cell Proliferation B-Lymphocytes 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 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 Treatment Efficacy Up-Regulation adult leukemia analog autocrine chemokine chemotherapy chronic T-cell leukemia effective therapy inhibitor/antagonist migration novel phosphoric diester hydrolase programs therapeutic target tool

项目摘要

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cAMP磷酸二酯酶（PDE4）抑制剂，如罗利普兰，在B细胞慢性淋巴细胞白血病中诱导细胞凋亡，即使在没有激活腺苷酸环化酶（如二萜福斯克林）的外源性药物的情况下。相反，T细胞或T- cll对罗利普兰诱导的细胞凋亡具有抗性。罗利普兰在B-CLL细胞中诱导线粒体死亡途径，部分原因可能是由于磷酸酶PP2A的激活和BAD的去磷酸化。值得注意的是，cAMP还可以通过EPAC1 （cAMP激活的Rap1 GDP交换因子）激活B-CLL的抗凋亡途径。B-CLL细胞在循环造血细胞中EPAC1的功能表达是独一无二的，这表明EPAC1信号可能在该疾病的病理生理中发挥作用。为了阐明PDE4抑制剂激活B-CLL线粒体凋亡途径的机制，我们将：a)确定PDE4抑制剂诱导的CLL细胞凋亡是否由pka介导。B)确定罗利普兰诱导的CLL细胞凋亡是否与epac无关。C)确定罗利普兰诱导CLL PP2A活性增强的机制。D)确定罗利普兰介导的CLL细胞凋亡是否需要PP2A。具体目标二。为了对比EPAC和PKA信号在CLL中的作用，我们将：A)确定PDE4抑制剂激活PKA是否会阻断EPAC激活增加B-CLL趋化因子转录水平的能力。B)确定epac诱导的趋化因子和/或Mcl-1转录物的增强是否是循环造血细胞中B- cll所特有的。C)确定epac诱导的B-CLL存活增加是否源于IL-8自分泌回路的上调。D)确定PKA和EPAC是否对PI3K或其下游靶点有差异调节。具体目标三。为了确定功能性EPAC在CLL细胞中的独特表达是否具有病理生理学意义，我们将：A)研究EPAC活化对CLL粘附和迁移的影响。B)比较EPAC和PKA激活对基础和化疗诱导的CLL生存的影响。C)比较EPAC和PKA对CLL和B细胞增殖的影响。