CYTOKINES IN GLIAL CELLS AND EAE BRAIN

促炎性细胞因子的存在及诱生作用 一氧化氮合酶在多发性硬化患者脑组织病变中的表达 硬化症(MS)提供了NO/ONOO‘和自由基的证据 氧(02-)在MS的病理生理学中起重要作用。 我们实验室的研究表明，蛋白质的cAMP抑制剂 磷酸酶1/2A调节NO的产生和iNOS的诱导 在星形胶质细胞和巨噬细胞中通过不同的机制。不会改变 细胞通过改变抗氧化酶的表达进行氧化还原。我们 还表明抗氧化剂(N-乙酰半胱氨酸)和甲氧戊酸 抑制剂(洛伐他汀和苯乙酸钠)可阻断 促炎细胞因子、诱导型一氧化氮合酶和一氧化氮的产生 激活培养的星形胶质细胞、巨噬细胞和小胶质细胞。 这项建议的目的是破译 PKA和PKA对星形胶质细胞和巨噬细胞诱导型一氧化氮合酶的影响 蛋白磷酸酶1/2A与诱导型一氧化氮合酶在疾病过程中的作用 实验性变态反应性脑炎(EAE)，MS的动物模型。 这些目标的实现将通过理解 分化诱导中NFkB活化的分子机制 蛋白激酶A和蛋白磷酸酶1/2A对星形胶质细胞诱导型一氧化氮合酶的影响 巨噬细胞。有人建议对蛋白质磷酸酶进行鉴定。 (蛋白磷酸酶I或蛋白磷酸酶2A)负责 诱导促炎细胞因子NFkB和激活 星形胶质细胞和巨噬细胞中的iNOS。NO/ONOO‘在细胞周期中的可能作用 将用小鼠模型研究EAE的病理生理学。 哪些缺乏iNOS(iNOS基因敲除)，哪些表达增加 诱导型一氧化氮合酶水平。我们还建议测试可能的治疗效果 抗氧化剂药物(N-乙酰半胱氨酸)和甲氧戊酸抑制剂 (洛伐他汀和苯乙酸钠)阻止/减缓进展 在EAE的疾病过程中。

The presence of proinflammatory cytokines and induction of inducible nitric oxide synthase (iNOS) in brain lesions of patients with multiple sclerosis (MS) provided evidence that NO/ONOO' along with free radicals of oxygen (02-) play an important role in the pathophysiology of MS. Studies from our laboratory have shown that cAMP inhibitors of protein phosphatases 1/2 A regulate the production of NO and induction of iNOS in astrocytes and macrophages by different mechanisms. NO alters the cellular redox by altering the expression of antioxidant enzymes. We have also shown that antioxidants (N-acetyl cysteine) and mevalonate inhibitors (lovastatin and sodium phenylacetate) block the induction of proinflammatory cytokines and that of iNOS and the production of NO in activated cultured astrocytes, macrophages and microglia. The objective of this proposal is to decipher the mechanism of the induction or regulation of iNOS in astrocytes and macrophages by PKA and protein phosphatases 1/2 A and the role of iNOS in the disease process of experimental allergic encephalitis (EAE), an animal model of MS. Achievement of these goals will be facilitated by understanding the molecular mechanism of activation of NFkB in the differential induction of iNOS by PKA and protein phosphatases 1/2 A in astrocytes and macrophages. Studies are proposed to identify the protein phosphatase (protein phosphatase I or protein phosphatase 2A) that is responsible for the induction of proinflammatory cytokines NFkB and activation of iNOS in astrocytes and macrophages. The possible role of NO/ONOO' in the pathophysiology of EAE will be investigated by using mice models which lack iNOS (iNOS knock out) and those which express increased levels of iNOS. We also propose to test the possible therapeutic effect of antioxidants drugs (N-acetylcysteine) and mevalonate inhibitors (lovastatin and sodium phenylacetate) in halting/slowing the progression of the disease process in EAE.