Regulation of Death Ligand-Induced Killing

死亡配体诱导杀伤的调控

• 批准号: 8884794
• 负责人: SCOTT H KAUFMANN
• 金额: $ 37.3万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-13 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8884794
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Affect; Allogenic; American; Antibodies; Apoptosis; Apoptotic; Attention; BCL2 gene; Binding; Biochemical Process; Biological; Caspase; Cell Death; Cell Surface Proteins; Cell surface; Cell-Mediated Cytolysis; Cells; Cessation of life; Chemotherapy-Oncologic Procedure; Chronic Lymphocytic Leukemia; Cleaved cell; Clinical; Clinical Trials; Combination Drug Therapy; Cytosol; DNA Damage; Data; Death Domain; Development; Dysmyelopoietic Syndromes; Exhibits; Eye; Family member; Farnesyl Transferase Inhibitor; Fc Receptor; Funding; Half-Life; Hematologic Neoplasms; Histone Deacetylase Inhibitor; Immune system; Immunologic Surveillance; Immunotherapy; In Vitro; Intervention; Ligand Binding; Ligands; Ligation; Lymphocyte; Lymphoma; Malignant Neoplasms; Measurement; Mediating; Messenger RNA; Mitochondria; Molecular; Natural Killer Cells; Necrosis; Outcome; Outer Mitochondrial Membrane; Pathway interactions; Patients; Phorbol Esters; Play; Poly(ADP-ribose) Polymerases; Positioning Attribute; Process; Protein Kinase C; Ptosis; RNA-Binding Proteins; Receptor Cell; Receptor Gene; Receptor Signaling; Regulation; Research Personnel; Retinoids; Role; Sampling; Signal Transduction; Sp1 Transcription Factor; Stem cell transplant; TNF-related apoptosis-inducing ligand; TNFRSF10A gene; TNFRSF10B gene; Testing; Therapeutic Agents; Time; Transactivation; Transcriptional Activation; Tumor Necrosis Factor Ligand Superfamily Member 6; Type I Epithelial Receptor Cell; Up-Regulation; Work; adapter protein; anticancer treatment; base; cancer cell; cancer immunotherapy; cancer therapy; caspase-3; caspase-8; chemotherapeutic agent; chemotherapy; chronic leukemia; cytotoxic; cytotoxicity; design; fluoropyrimidine; graft vs leukemia effect; improved; in vivo; inhibitor/antagonist; insight; interest; killings; monomer; neoplastic cell; novel; overexpression; pre-clinical; pro-caspase-8; promoter; public health relevance; receptor; receptor expression; research study; resistance mechanism; response; trafficking; tumor

 DESCRIPTION (provided by applicant): Because apoptosis, a biochemically distinct form of cell death, is one of the major responses triggered in cancer cells by either chemotherapy or immunotherapy, there has been substantial interest in understanding regulation of the apoptotic process. Studies performed over the past two decades have demonstrated that death receptors, a subfamily of the tumor necrosis factora receptor superfamily, play critical roles in the response to certain cancer chemotherapeutic agents, to death ligands such TNF-related apoptosis-inducing ligand (TRAIL) and Fas ligand, and to cytotoxic lymphocytes that express these ligands. Thus, improved understanding of factors that determine whether death receptor ligation will induce cell death or not has potential implications for certain aspects of both cancer chemotherapy and immunotherapy. Our preliminary studies have provided new insight into multiple different aspects of death receptor regulation. Working backwards from measurement of cell surface death receptors, we have shown that the outcome of death ligand signaling is impacted by factors that affect trafficking of death receptors to the cell surface, stability of deth receptor mRNA, and transcriptional activation of death receptor genes. To build on these observations, we now propose to 1) elucidate the pathway by which protein kinase C inhibits trafficking of death receptors to the cell surface, 2) investigate how death receptor mRNA half-life is regulated by RNA binding proteins to produce cells that exhibit Bcl-2 independent vs. Bcl-2 inhibitable death ligand- induced signaling, and 3) determine the mechanism by which PARP inhibitors, acting through the transcription factor Sp1, enhance death ligand-induced apoptosis in AML cells and clinical AML samples ex vivo. If successful, the proposed experiments will not only provide new insight into the regulation of death receptor-mediated apoptosis, but also generate preclinical data in further support of testing a novel death ligand/chemotherapy combination.

 描述（由申请人提供）：由于细胞凋亡（一种生物化学上不同的细胞死亡形式）是化疗或免疫治疗在癌细胞中引发的主要反应之一，因此对理解细胞凋亡过程的调控有很大兴趣。在过去的二十年中进行的研究表明，死亡受体，肿瘤坏死因子受体超家族的一个亚家族，在反应中发挥关键作用 某些癌症化疗剂、死亡配体如TNF α相关凋亡诱导配体（TRAIL）和Fas配体以及表达这些配体的细胞毒性淋巴细胞。因此，提高对决定死亡受体连接是否会诱导细胞死亡的因素的理解，对癌症化疗和免疫治疗的某些方面具有潜在的意义。我们的初步研究为死亡受体调控的多个不同方面提供了新的见解。从细胞表面死亡受体的测量向后工作，我们已经表明死亡配体信号传导的结果受到影响死亡受体向细胞表面的运输、死亡受体mRNA的稳定性和死亡受体基因的转录激活的因素的影响。为了建立在这些观察结果的基础上，我们现在提出1）阐明蛋白激酶C抑制死亡受体向细胞表面运输的途径，2）研究死亡受体mRNA半衰期如何被RNA结合蛋白调节以产生表现出Bcl-2非依赖性与Bcl-2可诱导的死亡配体诱导的信号传导的细胞，以及3）确定PARP抑制剂，通过转录因子Sp1起作用，增强AML细胞和临床AML样品中离体死亡配体诱导的细胞凋亡。如果成功，所提出的实验不仅将为死亡受体介导的细胞凋亡的调节提供新的见解，而且还将产生临床前数据，进一步支持测试新型死亡配体/化疗组合。