课题基金 / 基金详情

ROLE FOR CELL CYCLE PROTEINS IN HIV ENCEPHALITIS

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:
$5.0万
依托单位国家:
美国
项目类别:
财政年份:
2001
资助国家:
美国
项目状态:
已结题
起止时间:
2001-02-01 至 2001-08-31

项目摘要

项目成果

Kelly L Jordan-Sciutto的其他基金

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中文摘要
翻译
描述:艾滋病毒脑炎对神经元的损害和丧失是显着的。 神经胶质细胞不存在明显的 HIV 感染。神经元细胞死亡 据信是由激活的、感染 HIV 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。其中一些因素(包括 NTF)能够 诱导细胞周期调节机制的变化。我们观察到了变化 细胞三个关键调节因子的表达和亚细胞定位 循环,pRb。 HIV 脑炎 (HIVE) 模型中的 E2F1 和 p53。这导致了 我们提出这样的假设:在 HIVE 中观察到的神经元变性是 由终末期细胞周期机器活动的变化引起 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, 导致像视网膜母细胞瘤这样的口袋蛋白磷酸化 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,尤其是 E2F1。自从 pRb、E2F1 和 p53 控制着决定细胞存活的两条关键途径,我们 假设这些蛋白质活性的变化会改变神经元 生存能力。使用回顾性尸检研究和体外模型 HIVE,我们将研究这两个成员的活动和表达 途径及其对神经元和神经胶质元件存活的影响。我们的 第一个目标是确定 pRb 及其家族成员的调控 通过响应巨噬细胞分泌的因子而磷酸化。具体目标2 将确定 E2F1 活性是否被巨噬细胞分泌因子改变 信号传导并研究激活的 E2F1 对神经元和胶质细胞的影响 生存。最后,具体目标 3 将解决 p53 对 神经元和神经胶质细胞对巨噬细胞分泌因子的反应而存活。这些 具体目标将有助于确定细胞周期调节剂在神经元中的作用 HIVE 期间神经胶质细胞的存活,并确定治疗目标以破坏 导致相关神经退行性疾病的分子级联反应。
英文摘要
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.
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Penn Mental Health AIDS Research Center
  • 批准号:
    10819857
  • 项目类别:
  • 资助金额:
    $24.38万
  • 财政年份:
    2023
  • 负责人:
    Kelly L Jordan-Sciutto
  • 依托单位:
Inter- and Intra-cellular effects of cannabinoids, HIV and ART in the CNS
  • 批准号:
    10452486
  • 项目类别:
  • 资助金额:
    $70.81万
  • 财政年份:
    2020
  • 负责人:
    Kelly L Jordan-Sciutto
  • 依托单位:
Inter- and Intra-cellular effects of cannabinoids, HIV and ART in the CNS
  • 批准号:
    10618933
  • 项目类别:
  • 资助金额:
    $69.59万
  • 财政年份:
    2020
  • 负责人:
    Kelly L Jordan-Sciutto
  • 依托单位:
Role of PERK haplotypes in HIV-Associated Neurocognitive Disorders
  • 批准号:
    9317357
  • 项目类别:
  • 资助金额:
    $54.84万
  • 财政年份:
    2016
  • 负责人:
    Kelly L Jordan-Sciutto
  • 依托单位: