Role of cell cycle protein in HIV encephalitis

性状（由申请人提供）：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，其决定非神经元系统中的细胞结果。这使我们提出细胞周期蛋白在HIVE患者的神经元中表现出改变的活性，并且这种活性决定了响应于细胞外环境中存在的巨噬细胞分泌因子的冲击的神经元存活。我们已经观察到在HIVE和SIVE中pRb的磷酸化失活增加（ppRb）和细胞质E2 F1增加。使用体外培养，NTF和趋化因子刺激ppRb和细胞质E2 F1增加，但过氧化氢不。由于E2 F1分布和pRb磷酸化的变化发生在响应神经营养/生存信号的细胞中，而不是在响应氧化应激的细胞中，我们提出，在疾病中具有增加的ppRb和细胞质E2 F1的神经元是“存活”的神经元。这使我们假设E2 F1和ppRb决定神经元的活力依赖于它们的亚细胞分布和相互作用的合作伙伴，这是由细胞外环境中的主导信号线索。建议的目标如下：1）确定细胞质E2 F1是否提供对HIV相关毒素的神经保护，2）确定MDMx在调节细胞存活和E2 F1在响应神经保护因子与神经毒性因子的神经元中的亚细胞定位中的作用，及3）决定是否在─与那些响应毒性因子而被修饰的残基相比，响应营养因子而对pRb进行的翻译修饰发生在不同的氨基酸上。这些研究将阐明细胞周期蛋白在HIVE和其他具有炎症成分的神经退行性疾病中决定神经元存活的作用。

DESCRIPTION (provided by applicant): including chemokines, cytokines, neurotrophic factors (NTF), reactive oxygen species, and viral proteins. Most of these factors stimulate changes in cell cycle regulatory machinery which determines 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 chemokines stimulate increased ppRb and cytoplasmic 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 studies will elucidate the role of cell cycle proteins in determining neuronal survival in HIVE and other neurodegenerative diseases with inflammatory components.