ROLE FOR CELL CYCLE PROTEINS IN HIV ENCEPHALITIS

细胞周期蛋白在 HIV 脑炎中的作用

• 批准号: 6503798
• 负责人: Kelly L Jordan-Sciutto
• 金额: $ 5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6503798
• 关键词: AIDS dementia complex; Retroviridae; cell cycle proteins; chemokine; human fetus tissue; macrophage; mixed tissue /cell culture; monocyte chemoattractant protein 1; neurotrophic factors; p53 gene /protein; phosphorylation; postmortem; retinoblastoma protein; transcription factor; transfection /expression vector

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.

描述：HIV脑炎是一种值得注意的神经元损伤和损失， 神经胶质细胞没有明显的HIV感染。神经元细胞死亡 被认为是由活化的、HIV感染的巨噬细胞分泌的 产品包括趋化因子、细胞因子、神经营养因子（NTF），以及 喹啉酸其中包括NTF在内的几个因素有能力 诱导细胞周期调节机制的变化。我们观察到了一些变化 在表达和亚细胞定位的三个关键调节细胞 循环，pRb。E2 F1和p53在HIV脑炎（HIVE）模型中的作用。这导致 我们提出假设，在HIVE中观察到的神经元变性是 由细胞周期机制的活性变化引起， 分化的神经元细胞因子、趋化因子和神经营养因子的激活 非神经元系统中的因子受体导致第二信使级联， 导致口袋蛋白的磷酸化， 易感基因产物pRb。这些蛋白质的磷酸化导致 控制基因表达的蛋白质的失调，最明显的是E2F1。以来 pRb、E2F1和p53控制着决定细胞存活的两条关键通路， 假设这些蛋白质活性变化将改变神经元 生存能力。使用回顾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 第一个目标是确定pRb及其家族成员的调节 通过响应巨噬细胞分泌因子的磷酸化。具体目标2 将确定E2F1活性是否被巨噬细胞分泌因子改变 研究激活的E2F1对神经元和神经胶质细胞的影响。 生存最后，具体目标3将讨论p53对以下方面的贡献： 响应巨噬细胞分泌因子的神经元和神经胶质细胞存活。这些 具体的目标将有助于确定细胞周期调节剂在神经元细胞中的作用， 和胶质细胞存活，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。