课题基金 / 基金详情

The Cell-Cycle Control of Astrocytes and Astrocytomas

The Cell-Cycle Control of Astrocytes and Astrocytomas
星形胶质细胞和星形细胞瘤的细胞周期控制
批准号:
6762366
负责人:
DAVID E WEINSTEIN
金额:
$21.76万
依托单位:
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:
2001-07-15 至 2006-06-30

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中文摘要
翻译
描述(由申请人提供):今年,每年 在可预见的未来,17,000名美国人将患上原发性脑癌。的 这些,最常见的肿瘤是星形细胞瘤。在即将到来的8000人中 被诊断为星形细胞瘤,所有人最终都会死于自己的疾病。这个 星形胶质细胞对转化的脆弱性在于它有能力 在生物体生命周期的任何时刻重新进入细胞周期。尽管 在增殖能力方面,星形胶质细胞大部分保持静止,除非在 对疾病或创伤的反应,也就是伴随的神经元丢失。一个 几年前,我们和其他人证明了星形胶质细胞的增殖 控制是通过与神经细胞膜的接触来实现的,尽管精确的 神经元发挥这种控制作用的分子机制仍然难以捉摸。 我的实验室最近在细胞表面发现了一种受体 星形胶质细胞,CD8-1,这是神经元诱导星形胶质细胞必不可少的 细胞周期停滞(详见初步数据和后附手稿)。 在这一应用中,我们提出了一系列生化、分子和细胞 旨在鉴定和表征的生物学实验 神经元CD8-1结合蛋白。此外,我们将开始查询 神经元结合后的星形胶质细胞信号机制。我们的研究结果 星形胶质细胞表达CD8-1对神经元诱导生长控制的要求 具有额外的意义,基于我们的观察,所有 到目前为止,我们检测到的星形细胞瘤细胞系绝对下调了表达 CD8-1蛋白和信息。以确定CD8-1的表达是否可以挽救 这些细胞对由细胞周期停滞诱导的神经元做出反应的能力,我们 在星形细胞瘤细胞系中表达了CD8 1-GFP融合载体。这个 转染者将在体外和体内进行神经元反应性检测 肿瘤在裸鼠体内的进展和转移。与这些同时进行的 实验中,我们将继续进行一系列亲和层析纯化 神经元膜蛋白是星形胶质细胞的活性抑制物 扩散。虽然我们希望并期待我们的两条调查路线 控制星形胶质细胞生长的神经元介质将汇聚,这是相当的 我们可能会确定涉及的独立的、冗余的机制 在维持中枢神经系统的数量平衡方面。
英文摘要
DESCRIPTION (provided by applicant): This year, and in every year in the foreseeable future, 17,000 Americans will develop primary brain cancers. Of these, the most common tumor is astrocytoma. Of the 8,000 people to be diagnosed with astrocytoma, all will eventually die of their disease. The vulnerability of the astrocyte to transformation lies in its ability to re-enter the cell-cycle at any point in the life-time of an organism. In spite of the ability to proliferate, astrocytes are kept mostly quiescent, except in response to disease or trauma, where there is a concomitant neuronal loss. A number of years ago, we and others demonstrated that astrocyte proliferative control is effected by contact with neuronal membranes, although the precise molecular mechanism by which neurons exert this control has remained elusive. My laboratory has recently identified a receptor on the surface of the astrocyte, CD8 1, which is absolutely required for neuron-induced astrocyte cell-cycle arrest (see Preliminary Data, and appended manuscript for details). In this application, we propose a series of biochemical, molecular and cell biological experiments aimed at the identification and characterization of neuronal CD8 1 binding proteins. In addition, we will begin to query the astrocytic signaling mechanism following neuronal binding. Our findings for the requirement for astrocyte expressed CD8 1 for neuron-induced growth control takes on added significance, based on our observation that all of the astrocytoma cell lines we have examined to date have absolutely down regulated CD8 1 protein and message. To determine if CD8 1 expression can rescue the ability of these cells to respond to neuron-induced by cell-cycle arrest, we have expressed a CD8 1 -GFP fusion construct in the astrocytoma cell lines. The transfectants will be assayed for in vitro neuronal responsiveness, and in vivo tumor progression and metastasis in nude mice. In parallel with these experiments, we will continue a series of affinity chromatographic purification of neuronal membrane proteins that are active inhibitors of astrocyte proliferation. While we hope and anticipate that our two lines of inquiry on neuronal mediators of astrocyte growth control will converge, it is quite possible that we will identify separate, redundant mechanisms that are involved in maintaining CNS numerical homeostasis.
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海外基金