ROLE FOR CELL CYCLE PROTEINS IN HIV ENCEPHALITIS

描述：HIV脑炎是一种显著的神经细胞损伤和丢失。 没有明显的HIV感染神经胶质细胞。神经细胞死亡 被认为是由激活的、感染艾滋病毒的巨噬细胞分泌的 产品包括趋化因子、细胞因子、神经营养因子(NTF)和 喹啉酸。其中包括NTF在内的几个因素有能力 诱导细胞周期调控机制的变化。我们观察到了变化 细胞内三种关键调控因子的表达和亚细胞定位 循环，公共关系科。E2F1和P53，在HIV脑炎(HIVE)模型中。这导致了 美国将提出假设，即在蜂巢中观察到的神经元变性是 由终末期细胞周期机制的活性变化引起 分化的神经元。细胞因子、趋化因子的激活与神经营养 非神经系统中的因子受体导致第二信使级联， 导致像视网膜母细胞瘤这样的口袋蛋白的磷酸化 易感基因产物pRb。这些蛋白质的磷酸化导致 放松对控制基因表达的蛋白质的管制，最明显的是E2F1。自.以来 PRb、E2F1和P53控制着决定细胞存活的两个关键途径，我们 假设这些蛋白质活性的变化将改变神经元 生存能力。使用回溯性尸检研究和体外模型 蜂巢，我们将研究这两个成员的活动和表达 通路及其对神经元和神经胶质细胞存活的影响。我们的 第一个目标是确定对公共关系科及其家庭成员的监管 通过磷酸化反应巨噬细胞分泌的因子。具体目标2 将确定E2F1活性是否受巨噬细胞分泌因子的影响 激活的E2F1对神经元和胶质细胞的影响及其信号转导研究 生死存亡。最后，具体目标3将讨论P53对 巨噬细胞分泌因子对神经元和神经胶质细胞存活的影响。这些 特定的目标将有助于确定细胞周期调节器在神经元中的作用 和神经胶质细胞在蜂巢期间的存活，并确定治疗靶点以破坏 分子级联导致相关的神经退行性疾病。

DESCRIPTION: HIV encephalitis is remarkable for neuronal damage and loss in the absence of significant HIV infection of neuroglial cells. Neuronal cell death is believed to be mediated by activated, HIV-infected macrophagesecreted products including chemokines, cytokines, neurotrophic factors (NTF), and quinolinic acid. Several of these factors including NTF have the ability to induce changes in the cell cycle regulatory machinery. We have observed changes in expression and subcellular localization of three key regulators of the cell cycle, pRb. E2F1, and p53, in models for HIV encephalitis (HIVE). This has led us to propose the hypothesis that neuronal degeneration observed in HIVE is caused by changes in activity of cell cycle machinery in terminally differentiated neurons. Activation of cytokine, chemokine, and neurotrophic factor receptors in non-neuronal systems results in second messenger cascade, which result in phosphorylation of pocket proteins like the retinoblastoma susceptibility gene product, pRb. Phosphorylation of these proteins leads to deregulation of proteins controlling gene expression, most notably E2F1. Since pRb, E2F1 and p53 control the two key pathways determining cell survival, we hypothesize that changes in activity of these proteins will alter neuronal viability. Using both retrospective autopsy studies and an in vitro model of HIVE, we will study the activity and expression of members of these two pathways and their effects on survival of neuronal and glial elements. Our first aim focuses on determining the regulation of pRb and its family members by phosphorylation in response to macrophage secreted factors. Specific Aim 2 will determine if E2F1 activity is altered by macrophage secreted factor signaling and study the impact of activated E2F1 on neuronal and glial survival. Finally specific aim 3 will address the contribution of p53 to neuronal and glial survival in response to macrophage secreted factors. These specific aims will help define the role of cell cycle regulators in neuronal and glial survival during HIVE and define therapeutic targets to disrupt the molecular cascade leading to the associated neurodegenerative disease.