Involvement of Survivin in the Development of PML

Survivin 参与 PML 的发展

• 批准号: 7285346
• 负责人: Luis Del Valle
• 金额: $ 32.5万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 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/7285346
• 关键词: Involvement; Survivin; Development; PML

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一员，是公认的进行性多灶性白质脑病（PML）的病因，PML是一种致命的中枢神经系统（CNS）脱髓鞘疾病，常见于潜在免疫抑制患者。艾滋病大流行后，一度被认为是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被认为是艾滋病的决定性条件。初次感染后，病毒很可能在肾脏中处于潜伏状态，在免疫抑制下进入大脑，并在中枢神经系统的髓磷脂产生细胞少突胶质细胞中有效地复制，并失败地感染星形胶质细胞。在JCV感染引起的损伤中，少突胶质细胞的溶解破坏和星形胶质细胞的激活导致PML的特征性组织病理学标志，即大面积髓磷脂丢失，其中可以发现许多具有非典型和多形性核的奇异星形胶质细胞，以及核内嗜酸性包涵体的增大的少突胶质细胞。处理受损或感染细胞的自然反应是程序性细胞死亡。细胞死亡与存活的复杂机制取决于促凋亡蛋白与凋亡抑制剂之间的微妙平衡。我们在PML患者脑样本中的初步免疫组织化学数据显示，在奇异星形胶质细胞和JCV感染的少突胶质细胞的核内包体中，凋亡抑制剂家族成员Survivin的表达增加。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。人们认为，细胞凋亡抑制的机制与半胱天蛋白酶失活有关，半胱天蛋白酶是细胞程序性死亡的执行蛋白。Western blot和免疫细胞化学结果显示，JCV感染的原代少突胶质细胞培养物中Survivin的表达增强。此外，对感染细胞的细胞周期分析表明，凋亡细胞数量减少，siRNA抑制Survivin导致细胞凋亡急剧增加。这些结果表明，JCV感染可刺激Survivin的表达，抑制细胞凋亡，刺激细胞存活，从而与感染周期竞争。