GLOBOID CELL LEUKODYSTROPHY

描述：(逐字摘自申请者摘要)Globoid单元格 白细胞增多症是一种常染色体代谢性疾病。 进行性病因性β-半乳脑苷酶缺乏症 神经氨酸(半乳糖鞘氨醇)的积累，随后成为一种 神经炎性疾病导致脱髓鞘、胶质细胞丢失和 死亡。 拟议研究的目标是阐明以下可能的作用 精神药物在神经炎性反应中的作用及其机制 球状细胞小鼠模型Twitcher鼠的少突胶质细胞丢失 白质营养不良(GLD)。我们实验室的研究已经证明 精神病素增强细胞因子诱导的iNOS的诱导 精神病素与C6神经胶质细胞孵育时，可诱导细胞凋亡 细胞丢失。这些目标的实现将通过理解 诱导型一氧化氮合酶(INOS)诱导的分子机制 炎性细胞因子(如肿瘤坏死因子α和白介素6)与精神药物诱导 少突胶质细胞的凋亡性丢失。还建议进行研究以调查 精神药物引起的脑细胞/脑内电生理改变 切片来自抽搐小鼠。我们还建议测试抗氧化剂的有效性。 (N-乙酰半胱氨酸、α-硫辛酸)和已知的 阻断炎性细胞因子(洛伐他汀、钠 苯乙酸酯)，用于阻止/延缓抽搐小鼠的疾病进程。 拟议的研究将提供对疾病过程的更好了解。 在GLD/Twitcher小鼠中的作用和药物有益效应的演示 在抽动小鼠中)可能有助于识别理想的候选药物 随后在涉及GLD患者的临床试验中使用。

DESCRIPTION: (Verbatim from the Applicant's Abstract) Globoid cell leukocystorophy (Krabbe's Disease) is an autosomal metqabolic disordear of beta-galactocerebrosidase deficiency with progressive pathognomonic accumulation of psychosine (galactosylsphingosine) which subsequently becomes a neuroinflammatory disease resulting in demyelination, olidogendrocyte loss and death. The objectives of the proposed studies are to elucidate the possible role of psychosine in neuroinflammatory response and in the mechanism of oligodendrocyte loss by using twitcher mice, a murine model of globoid cell leukodystrophy (GLD). Studies from our laboratory have demonstrated the psychosine potentiates the cytokine-induced induction of iNOS and also the psychosine when incubated with C6 glial cells in culture, induces apoptotic cell loss. Achievement of these goals will be facilitated by understanding the molecular mechanism of induction of inducible nitric oxide synthase (iNOS) and inflammatory cytokines (e.g. TNFalpha and IL-6) and psychosine-induced apoptotic loss of oligodendrocytes. Studies are also proposed to investigate the psychosine-induced electrophysiological alterations in brain cells/brain slices form twitcher mice. We also propose to test the efficacy of antioxidants (N-acetyl cysteine, alpha-lipoic acid) and the compounds that are known to block the induction of inflammatory cytokines (lovastatin, sodium phenylacetate) for halting/delaying the disease process in twitcher mice. The proposed studies will provide a better understanding of the disease process in GLD/twitcher mice and the demonstration of beneficial effects of the drugs in twitcher mice) may help in the identification of an ideal candidate drug for subsequent use in clinical trials involving GLD patients.