Involvement of Survivin in the Development of PML

Survivin 参与 PML 的发展

• 批准号: 8066552
• 负责人: Luis Del Valle
• 金额: $ 29.7万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8066552
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Apoptosis; Apoptosis Inhibitor; Apoptotic; Appearance; Area; Astrocytes; Attention; Binding; Biological Assay; Brain; Caspase; Cell Count; Cell Culture Techniques; Cell Cycle; Cell Cycle Arrest; Cell Death; Cell Nucleus; Cell Survival; Cells; Characteristics; Clinical; Cytochromes; DNA; DNA Damage; DNA Repair; DNA-Binding Proteins; Data; Development; Disease; Doctor of Medicine; Double Strand Break Repair; Down-Regulation; Embryo; Equilibrium; Evaluation; Event; Experimental Designs; Family; Gastrointestinal tract structure; Gene Expression; Gene Family; Genes; Genetic Transcription; Genome; Immune response; Immunosuppression; Immunosuppressive Agents; Inclusion Bodies; Infection; Inhibition of Apoptosis; JC Virus; Kidney; Literature; Lymphocyte; Lytic; Lytic Phase; M cell; Mediating; Messenger RNA; Mitosis; Molecular; Myelin; Neuraxis; Neuroglia; Nonhomologous DNA End Joining; Nuclear; Nuclear Inclusion; Oligodendroglia; Pathway interactions; Patients; Plasmids; Prevention; Principal Investigator; Progressive Multifocal Leukoencephalopathy; Proliferating; Promoter Regions; Protein Family; Proteins; RNA; Rare Diseases; Regulation; Reporting; Research Personnel; Resistance; Role; Sampling; Series; Small Interfering RNA; Specificity; TP53 gene; TdT-Mediated dUTP Nick End Labeling Assay; Techniques; Time; Tissues; Transfection; Up-Regulation; Viral; Viral Proteins; Viral Tumor Antigens; Virus; Virus Diseases; Western Blotting; accomplished suicide; base; cell injury; central nervous system demyelinating disorder; effective therapy; genetic regulatory protein; homologous recombination; immunocytochemistry; leukemia/lymphoma; member; pandemic disease; prevent; pro-apoptotic protein; programs; promoter; research study; respiratory; response; response to injury; sialosyl-T antigen; survivin; viral DNA

DESCRIPTION (provided by applicant): JC Virus, a member of the Polyomaviridiae family, is the well-established etiological agent of Progressive Multifocal Leukoencephalopathy (PML), a fatal demyelinating disease of the Central Nervous System (CNS), frequently seen in patients with underlying immunosuppressive conditions. After the AIDS pandemic, cases of PML, once considered a rare disease associated with leukemias and lymphomas, has dramatically ncreased and now, PML is considered and AIDS defining condition. After primary infection the virus remains in latent state most likely in the kidney, and under immunosuppression enters the brain and efficiently replicates in oligodendrocytes, the myelin producing cells of the CNS ad abortively infects astrocytes. The lytic destruction of oligodendrocytes and the activation of astrocytes in response to injury caused y JCV infection, result in the characteristic histopathological landmarks of PML, extensive areas of myelin loss, in which numerous bizarre astrocytes with atypical and pleomorphic nuclei, and enlarged oligodendrocytes harboring intra-nuclear eosinophilic inclusion bodies can be found. The natural response to dispose of damaged or infected cells is programmed cell death. The intrincate mechanisms that will decide between cell death and cell survival depend on the delicate balance between pro-apoptotic proteins and inhibitor of apoptosis. Our preliminary immunohistochemical data in brain samples from patients with PML revealed increased expression of Survivin, a member of the inhibitors of apoptosis family, in bizarre astrocytes and in the intra-nuclear inclusion bodies of JCV infected oligodendrocytes. This protein is abundantly expressed during development in embryonic proliferating tissues, but is absent in terminally differenciated cells. It is believed that the mechanism of apoptosis inhibition involves the inactivation of caspases, the programmed cell death executioner proteins. Our results also show that JCV infected primary oligodendroglial cell cultures show enhanced expression of Survivin by Western blot and immunocytochemistry. In addition cell cycle analysis of infected cells demonstrated a reduction in the number of apoptotic cells and siRNA inhibition of Survivin resulted in a dramatic increase in apoptosis. These results suggest that JCV infection stimulates the expression of Survivin, which prevents apoptosis, and stimulates cell survival in order to compete its infectious cycle.

描述（由申请人提供）：JC 病毒是多瘤病毒科的成员，是进行性多灶性白质脑病 (PML) 的公认病原体，PML 是一种致命的中枢神经系统 (CNS) 脱髓鞘疾病，常见于患有潜在免疫抑制疾病的患者。艾滋病大流行后，曾经被认为是一种与白血病和淋巴瘤相关的罕见疾病的 PML 病例急剧增加，现在 PML 被认为是艾滋病的定义性疾病。初次感染后，病毒最有可能在肾脏中保持潜伏状态，在免疫抑制下进入大脑并在少突胶质细胞（中枢神经系统的髓鞘生成细胞）中有效复制，并且无法感染星形胶质细胞。少突胶质细胞的裂解性破坏和星形胶质细胞对 JCV 感染引起的损伤的活化，导致 PML 的特征性组织病理学标志，大面积的髓磷脂丧失，其中大量具有非典型和多形性细胞核的奇异星形胶质细胞，以及含有核内嗜酸性包涵体的增大的少突胶质细胞 可以找到尸体。处理受损或受感染细胞的自然反应是程序性细胞死亡。决定细胞死亡和细胞存活的复杂机制取决于促凋亡蛋白和凋亡抑制剂之间的微妙平衡。我们对 PML 患者脑样本的初步免疫组织化学数据显示，在奇怪的星形胶质细胞和 JCV 感染的少突胶质细胞的核内包涵体中，Survivin（细胞凋亡抑制剂家族的成员）表达增加。该蛋白在胚胎增殖组织的发育过程中大量表达，但在终末分化细胞中不存在。据信，细胞凋亡抑制的机制涉及半胱天冬酶（程序性细胞死亡执行蛋白）的失活。我们的结果还表明，通过蛋白质印迹和免疫细胞化学，JCV 感染的原代少突胶质细胞培养物显示 Survivin 表达增强。此外，受感染细胞的细胞周期分析表明，凋亡细胞数量减少，Survivin 的 siRNA 抑制导致细胞凋亡急剧增加。这些结果表明，JCV 感染刺激 Survivin 的表达，从而防止细胞凋亡，并刺激细胞存活以完成其感染周期。