GLOBOID CELL LEUKODYSTROPHY

描述：（逐字摘自申请人摘要） 白细胞增多症（克拉伯病）是一种常染色体代谢性疾病， β-半乳糖苷酶缺乏症伴进行性特征性 积累的psychosine（半乳糖基鞘氨醇），随后成为 神经炎性疾病导致脱髓鞘、少突胶质细胞损失和 死亡 拟议研究的目的是阐明 精神分裂素在神经炎症反应中的作用及其机制 使用Twitcher小鼠（球状细胞的小鼠模型）进行少突胶质细胞损失 脑白质营养不良（GLD）。我们实验室的研究表明， Psychosine增强了马槟榔碱诱导的iNOS诱导， 当与培养的C6神经胶质细胞一起孵育时， 细胞丢失。通过了解以下方面，将有助于实现这些目标： 诱导型一氧化氮合酶（iNOS）诱导的分子机制， 炎性细胞因子（例如TNF α和IL-6）和精神分裂素诱导的 少突胶质细胞的凋亡损失。还建议进行研究， 精神病碱诱导的脑细胞电生理学改变/脑 切片来自抽搐小鼠。我们还建议测试抗氧化剂的功效 （N-乙酰半胱氨酸，α-硫辛酸）和已知的化合物， 阻断炎性细胞因子（洛伐他汀，钠 苯乙酸酯）用于停止/延迟抽搐小鼠中的疾病过程。 拟议的研究将提供对疾病过程的更好理解 在GLD/twitcher小鼠中的作用以及药物有益作用的证明 在抽搐小鼠）可能有助于确定一个理想的候选药物， 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.