DISREGULATION OF NEURONAL GSK-3BETA BY PAF
DISREGULATION OF NEURONAL GSK-3BETA BY PAF
批准号:
6394488
负责人:
Stephen Dewhurst
金额:
$27.91万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2000
资助国家:
美国
项目状态:
已结题
起止时间:
2000-07-01 至 2004-06-30
中文摘要
描述(改编自申请者摘要):血小板活化因子
纤溶酶原激活剂(PAF)是一种具有生物活性的磷脂,在中枢神经系统中起着多种作用。
神经系统(CNS)。一些病理事件,包括癫痫发作,
缺血和炎症反应导致PAF的突触聚集。
在这种情况下,PAF可以作为神经元损伤的中介物。超标水平
PAF也可能通过抑制中枢神经系统的正常发育而干扰中枢的正常发育
神经元迁移(例如,在Miller-Dieker的背景下
无脑畸形)。
我们的初步研究表明,PAF可以上调血管活性。
原代神经元中糖原合成酶3-β(GSK-3b)的表达。这可能是
与PAF对神经元存活和迁移的影响有关,因为
GSK-3b参与了轴突重塑和
神经细胞骨架,也是因为GSK-3b的激活(过度表达)
已被证明可导致PC12细胞的凋亡。因此,我们
假设PAF对GSK-3b的影响可能与其神经毒性有关
它的活性及其扰乱神经元迁移的能力。这项研究建议
在本申请中旨在通过实验验证这一假设。第一,
PAF介导的血管紧张素转换酶激活的分子机制
神经元GSK-3b,将被描述(目标1)。第二,实验将是
来检验GSK-3b需要激活的假设
PAF介导的神经毒性(AIM 2)。最后,将进行研究,以
确定PAF介导的GSK-3b是否也需要激活
神经元迁移中断(目标3)。总而言之,这些实验是
预计将为GSK-3b活动的监管提供新的见解
以及GSK-3b在介导PAF的作用中可能发挥的作用。
神经元存活和神经元迁移。
英文摘要
DESCRIPTION (adapted from applicant's abstract): Platelet activating factor
(PAF) is a bioactive phospholipid which plays a variety of roles in the central
nervous system (CNS). A number of pathologic events, including seizures,
ischemia and inflammatory reactions lead to the synaptic accumulation of PAF.
In this setting, PAF can act as a mediator of neuronal injury. Excessive levels
of PAF may also interfere with the normal development of the CNS, by inhibiting
neuronal migration (for example, in the context of Miller-Dieker
lissencephaly).
Our preliminary studies have shown that PAF can upregulate the activity of
glycogen synthase kinase 3-beta (GSK-3b) in primary neurons. This may be
relevant to PAF's effects on neuronal survival and neuronal migration because
GSK-3b has been implicated in axonal remodeling and in the regulation of the
neuronal cytoskeleton, and also because activation (over expression) of GSK-3b
has been demonstrated to lead to apoptosis of PC12 cells. We therefore
hypothesize that PAF's effects on GSK-3b may contribute both to its neurotoxic
activity and to its ability to disrupt neuronal migration. The studies proposed
in this application are intended to experimentally test this hypothesis. First,
the molecular mechanisms, which contribute to PAF-mediated activation of
neuronal GSK-3b, will be delineated (Aim 1). Second, experiments will be
conducted; to test the hypothesis that GSK-3b activation is required for
PAF-mediated neurotoxicity (Aim 2). Finally, studies will be performed to
determine whether GSK-3b activation is also required for PAF-mediated
disruption of neuronal migration (Aim 3). Taken together, these experiments are
expected to provide new insights into the regulation of GSK-3b activity in
neurons, and into the role that GSK-3b may play in mediating PAF's effects on
neuronal survival and neuronal migration.
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