Role of cell cycle protein in HIV encephalitis

HIV脑炎中的神经元死亡由活化的HIV感染的巨噬细胞分泌产物介导 包括趋化因子、细胞因子、神经营养因子（NTF）、活性氧和病毒蛋白。 这些因素中的大多数刺激细胞周期调节机制的变化， 非神经系统的结果。这使我们提出细胞周期蛋白表现出改变的活性 在HIVE患者的神经元中，这种活性决定了神经元对冲击的反应 巨噬细胞分泌的因子存在于细胞外环境中。我们观察到失活增加 在HIVE和SIVE中，pRb通过磷酸化（ppRb）和细胞质E2 F1增加。使用体外 培养物，NTF和趋化因子刺激ppRb和细胞质E2 F1增加，但过氧化氢 并没有。因为E2 F1分布和pRb磷酸化的变化发生在对E2 F1的反应的细胞中。 神经营养/生存信号，但不是在细胞对氧化应激反应，我们建议，神经元在 ppRb和细胞质E2 F1增加的疾病是“存活”的神经元。这让我们假设 E2 F1和ppRb决定神经元活力依赖于它们的亚细胞分布和相互作用 这是由细胞外环境中的主要信号线索决定的。以下目标 1）确定细胞质E2 F1是否提供对HIV相关的神经保护作用。 2）为了确定MDMx在调节细胞存活和E2 F1亚细胞定位中的作用， 神经元对神经保护因子和神经毒性因子的反应，以及3）确定是否翻译后 pRb响应营养因子的修饰发生在不同的氨基酸上， 对有毒因素作出反应的残留物。这些研究将阐明细胞周期蛋白在 确定HIVE和其他具有炎症成分的神经退行性疾病中的神经元存活。

Neuronal death in HIV encephalitis is mediated by activated, HIV-infected macrophage-secreted products including chemokines, cytokines, neurotrophic factors (NTF), reactive oxygen species, and viral proteins. Most of these factors stimulate changes in cell cycle regulatory machinery which determnes cellular outcomes in non-neuronal systems. This has led us to propose that cell cycle proteins exhibit altered activity in neurons of patients with HIVE and this activity determines neuronal survival in response to the onslaught of macrophage secreted factors present in the extracellular milieu. We have observed increased inactivation of pRb by phosphorylation (ppRb) and increased cytoplasmic E2F1 in HIVE and SIVE. Using in vitro cultures, NTF and chemokiens stimulate increased ppRb and cytoplaasmic E2F1, but hydrogen peroxide does not. Because the changes in E2F1 distribution and pRb phosphorylation occur in cells responding to neurotrophic/survival signals, but not in cells responding to oxidative stress, we propose that neurons in the disease with increased ppRb and cytoplasmic E2F1 are "surviving" neurons. This has led us to hypothesize that E2F1 and ppRb determine neuronal viability dependent on their subcellular distribution and interaction partners which is determined by the prevailing signaling cues in the extracellular milieu. The following aims are proposed: 1) To determine whether cytoplasmic E2F1 provides neuroprotection from HIVE-associated toxins, 2) To determine the role of MDMx in regulating cell survival and E2F1 subcellular localization in neurons responding to neuroprotective versus neurotoxic factors, and 3) To determine if post-translational modification of pRb in response to trophic factors occurs on different amino acids as compared to those residues modified in response to toxic factors. These stuidies will elucidate the role of cell cycle proteins in determining neuronal survival in HIVE and other neurodegenerative diseases with inflammatory components.