MECHANISMS OF RETROVIRUS INDUCED T AND NEURAL CELL DEATH

描述：本提案的主要研究目标是了解 神经免疫变性（NID）的发病机制 突变的莫洛尼鼠白血病病毒，ts 1。 与艾滋病毒感染一样，ts 1 小鼠感染引起T细胞的直接杀伤和间接杀伤 的神经元。 后者很可能是由于失去了联合国的基本支持。 感染的神经胶质细胞 导致细胞凋亡的机制 以及HIV或ts 1感染中出现的神经元丢失尚不清楚。 病毒 包膜蛋白显然在HIV -1和 ts 1介导的NID。 ts 1的env基因中的一个氨基酸替换 导致gPr 80 env从内质网的低效转运 内质网（ER）的高尔基体。 这种突变也被 与ts 1诱导NID的能力相关。 在受感染的T细胞和星形胶质细胞中 ts 1 gPr 80 env的低效运输特别严重，导致 gPr 80 env在ER中的积累。 工作假设为：（1）ER 是ts 1 env介导的细胞凋亡作用启动的主要位点; (2)ts 1包膜蛋白可能与质膜相互作用， 干扰负责触发细胞凋亡的受体信号传导;和 (3)ts 1可以直接激活ICE蛋白酶家族， 凋亡 研究者建议描述T细胞免疫相关的机制。 和TS 1诱导的星形胶质细胞死亡。 具体目标是：1）确定 gPr 80 env介导的细胞死亡机制; 2）鉴定下游的 可能参与ts 1介导的细胞死亡途径的因子; 3）确定 ICE细胞死亡途径是否在ts 1介导的NID中被利用， 评价ts 1感染ICE纯合子患者的临床疾病进展 （-/-）、杂合（+/-）和野生型（+/+）小鼠; 4）确定 ICE在ts 1介导的间接神经元死亡中的作用;以及5）确定 Bcl-2在神经元中的过表达可以保护ts 1诱导的 神经变性

DESCRIPTION: The primary research goal of this proposal is to understand the pathogenic mechanism of neuroimmunodegeneration (NID) induced by a mutant of the Moloney murine leukemia virus, ts1. As in HIV infection, ts1 infection of mice causes the direct killing of T cells and indirect killing of neurons. The latter is likely due to loss of essential support by the infected glial cells. The mechanism that leads to the apoptotic cell death and neuronal loss seen in HIV or ts1 infection are unclear. The viral envelope protein apparently plays an important role in both HIV - and ts1-mediated NID. A single amino acid substitution in the env gene of ts1 is responsible for inefficient transport of gPr80env from the endoplasmic reticulum (ER) to the Golgi apparatus. This mutation has also been correlated to ts1 ability to induce NID. In infected T cells and astrocytes the inefficient transport of ts1 gPr80env is particularly severe, resulting in accumulation of gPr80env in the ER. The working hypotheses are: (1) ER is the primary site where ts1 env-mediated apoptotic effects are initiated; (2) The ts1 envelope protein may interact with the plasma membrane and interfere with receptor signaling responsible for triggering apoptosis; and (3) ts1 may directly activate the ICE family of proteases to trigger apoptosis. The investigator proposes to characterize the mechanisms involved in T-cell and astrocyte death induced by ts1. The specific aims are to: 1) Determine the mechanisms of gPr80env-mediated cell death; 2) identify the downstream factors possibly involved in ts1-mediated cell-death pathways; 3) Determine whether the ICE cell death pathway is utilized in ts1-mediated NID by evaluating clinical disease progression in ts1-infected ICE homozygous (-/-), heterozygous (+/-) and wild type (+/+) mice; 4) Determine the role of ICE in ts1-mediated indirect neuronal death; and 5) Determine whether overexpression of Bcl-2 in neurons can protect against ts1-induced neurodegeneration.