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The Role of MKPs in Oxidative Neuronal Cell Death

The Role of MKPs in Oxidative Neuronal Cell Death
MKP 在氧化性神经细胞死亡中的作用
批准号:
6933906
负责人:
DAVID J LEVINTHAL
金额:
$4.51万
依托单位国家:
美国
项目类别:
财政年份:
2002
资助国家:
美国
项目状态:
已结题
起止时间:
2002-06-01 至 2006-05-31

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中文摘要
翻译
由缺血引起的许多神经元损伤不是立即的,而是延迟的,并且被认为是由于除了兴奋性毒性细胞死亡之外,压倒性的氧化应激和随后的凋亡。类似地,其他使人衰弱的疾病,如帕金森病和阿尔茨海默病,也与慢性氧化应激和神经退化有关。本提案的目的是研究神经元氧化应激期间发生的信号事件,并构思可以预防这种情况下神经元死亡的方法。谷氨酸诱导的氧化毒性,无论是在小鼠海马细胞系,HT 22,和初级未成熟的神经元皮质神经元,是一个充分研究的氧化应激和神经元细胞死亡的模型。丝裂原活化蛋白激酶(MAPK)磷酸酶(MKPs)在神经元氧化应激中的作用知之甚少。我们计划在HT 22和原代皮层神经元中研究谷氨酸诱导的氧化应激过程中MKPs表达和活性的变化。此外,将MKP 3及其无催化活性突变体MKP 3 C293 S转染到两种细胞系统中,以研究该磷酸酶消除谷氨酸诱导的氧化毒性的能力。涉及构建配体诱导的MKP 3-雌激素受体配体结合结构域(MKP 3-ER LBD)的进一步实验将允许响应于他莫昔芬的MKP 3活性的时间控制。
英文摘要
Much of the neuronal damage resulting from ischemia is not immediate but delayed and is thought to be due, in addition to excitotoxic cell death, to overwhelming oxidative stress and subsequent apoptosis. Similarly, other debilitating diseases such as Parkinson's Disease and Alzheimer's Disease have been linked with chronic oxidative stress and neurodegeration. It is the purpose of this proposal to investigate the signaling events that occur during oxidative stress in neurons and to conceive of approaches that may prevent neuronal death in this context. Glutamate-induced oxidative toxicity, both in the mouse hippocampal cell line, HT22, and primary immature neuronal cortical neurons, is a well-studied model of oxidative stress and neuronal cell death. Little is known about the role of the mitogen-activated protein kinase (MAPK) phosphatases (MKPs) during oxidative stress in neurons. We plan to investigate changes of expression and activity of MKPs during glutamate-induced oxidative stress in both HT22 and primary cortical neurons. In addition, MKP3 and its catalytically inactive mutant, MKP3 C293S, will be transfected into both cell systems in order to investigate the ability of this phosphatase to abrogate glutamate-induced oxidative toxicity. Further experiments involving the construction of a ligand- inducible MKP3-estrogen receptor ligand-binding domain (MKP3-ER LBD) will allow the temporal control of MKP3 activity in response to tamoxifen.
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