GLYCOSPHINGOLIPIDS IN MURINE NEURODEGENERATIVE DISEASES

描述（来自申请人的摘要）：鞘糖脂（GSL）是 富含质膜并包含神经节苷脂和中性 鞘糖脂婴儿型和幼年型神经节苷脂沉积症 疾病（GM 1和GM 2神经节苷脂沉积症）表现为严重的精神和运动 主要由于神经节苷脂引起的出生后几年内的变性 在大脑中积累。由于复杂的GSL是在 哺乳动物胚胎发育的早期阶段， 神经节苷脂蓄积将在胎儿发育期间开始， 在出生后的大脑中。因此，有效的治疗策略需要 积极的早期干预。本申请的目的是评估 NB-DGJ对胚胎期和哺乳期鞘糖脂代谢的影响 出生后的大脑发育NB-DGJ（N-丁基脱氧半乳糖野尻霉素）是一种 神经酰胺特异性葡萄糖基转移酶的水溶性抑制剂， 鞘糖脂（GSL）生物合成酶。初步调查结果显示 NB-DGJ可以抑制GSL生物合成而不改变活力， 培养的小鼠全胚胎器官发生阶段的形态发生。此外，委员会认为， 我们的合作者表明，NB-DGJ的结构异构体可以防止 成年Tay-Sachs小鼠中的溶酶体储存，并可减少神经功能 青少年Sandhoff病小鼠的异常。在此之前 NB-DGJ对小鼠胃肠道组成和形态发生的影响 哺乳动物胚胎在子宫内或出生后早期脑中生长 发展本研究将首次研究：1） NB-DGJ对小鼠模型胚胎和出生后脑GSL组成的影响 2）NB-DGJ处理对胚胎和 出生后脑发育，以及3）是否胚胎和出生后NB-DGJ 治疗对大脑发育、神经化学和 行为GSL的含量和分布将在神经和 对照和NB-DNJ处理小鼠的非神经组织。胚胎和出生后 脑发育将从形态学、组织学和 生化测量。由于没有有效的治疗方法， 神经节苷脂储存疾病，拟议的研究可以提供一种新的治疗方法， 对于这些神经退行性疾病的早期干预。

DESCRIPTION (From the Applicant's Abstract): Glycosphingolipids (GSLs) are enriched in plasma membranes and comprise the gangliosides and the neutral glycosphingolipids. The infantile and juvenile forms of the ganglioside storage diseases (GM1 and GM2 gangliosidoses) present with severe mental and motor degeneration within the first few years of birth due largely to ganglioside accumulation in the brain. Since complex GSLs are actively synthesized during early stages of mammalian embryonic development, neuropathology associated with ganglioside accumulation will commence during fetal development and will worsen in the postnatal brain. An effective treatment strategy would therefore require aggressive early intervention. The objective of this application is to evaluate the effects of NB-DGJ on glycosphingolipid metabolism during embryonic and postnatal brain development. NB-DGJ (N-butyldeoxygalactonojirimycin) is a water-soluble inhibitor of the ceramide specific glucosyltransferase, a key enzyme for glycosphingolipid (GSL) biosynthesis. Preliminary findings indicate that NB-DGJ can inhibit GSL biosynthesis without altering viability or morphogenesis in the organogenesis stage cultured whole mouse embryo. Moreover, our collaborators showed that a structural isomer of NB-DGJ could prevent lysosomal storage in adult Tay-Sachs mice and could reduce neurological abnormalities in juvenile Sandhoff disease mice. There have been no prior studies on the effects of NB-DGJ on the GSL composition and morphogenesis in the mammalian embryo growing in utero or during early postnatal brain development. This research will examine for the first time: 1) the effects of NB-DGJ on the GSL composition of embryonic and postnatal brains in mouse models of the gangliosidoses, 2) the influence of NB-DGJ treatment on embryonic and postnatal brain development, and 3) whether embryonic and postnatal NB-DGJ treatment has long-lasting effects on brain development, neurochemistry, and behavior. The content and distribution of GSLs will be measured in neural and nonneural tissues of control and NB-DNJ-treated mice. Embryonic and postnatal brain development will be assessed from morphological, histological, and biochemical measurements. Since there are no effective treatments for human ganglioside storages disease, the proposed research could offer a novel therapy for the early intervention of these neurodegenerative disorders.