Glycosphingolipids in murine neurodegenerative diseases

描述（由申请人提供）：本研究的目的是开发一种有效的神经节苷脂储存病的终身治疗方法。神经节苷脂剂量是一组无法治愈的神经退行性疾病，涉及溶酶体中神经节苷脂GM1或GM2的储存。GM1神经节苷脂病是由分解神经节苷脂GM1的酸性b-半乳糖苷酶的遗传缺陷引起的，而Sandhoff病（SD）是由分解神经节苷脂GM2的b-己糖苷酶b亚基的遗传缺陷引起的。神经节苷脂在这些疾病中的积累导致神经元死亡、炎症和进行性神经退化。我们的研究将涉及疾病管理的多种互补方法。本研究将评估NB-DGJ作为底物还原疗法，神经干细胞（NSCs）作为交叉矫正疗法，热量限制（CR）作为抗炎疗法。NB-DGJ降低糖鞘脂（GSL）的生物合成速率，从而抵消分解代谢的受损速率。NSCs提供缺失的溶酶体酶，从而减少GSL储存，而CR通过影响中枢神经系统炎症过程来改善健康。目的1将确定NB-DGJ对正常小鼠、GM1神经节脂质病和SD突变体出生后大脑GSL组成的影响。该目的将确定：a) NB-DGJ治疗后脑神经节苷脂恢复的时间和程度，b) GSL合成抑制延迟CNS组织病理神经节苷脂储存的程度，以及c) GSL合成抑制是否延迟储存病小鼠的髓磷脂异常。目的2将评估神经干细胞（NSC）单独移植和与NB-DGJ联合移植对发育中的SD小鼠的治疗潜力。我们假设NSCs将与NB-DGJ协同作用，以减少积累的gsl并提供最大的治疗效果。目的3将研究NB-DGJ在子宫内给药后对胚胎神经节苷的影响。这些研究将测试定时释放药物用于子宫内底物减少治疗GM1神经节脂质中毒的可行性。目的4将验证CR减少中枢神经系统炎症的假设，以及CR和NB-DGJ在控制中枢神经系统炎症、神经节苷脂积累和疾病进展方面的协同作用。提出的研究将为神经节苷脂沉积病的联合治疗提供必要的信息，并将对临床有转化效益。

DESCRIPTION (provided by applicant): The objective of this research is to develop an effective life long therapy for ganglioside storage diseases. The gangliosidoses are a group of incurable neurodegenerative diseases involving storage of either ganglioside GM1 or GM2 in lysosomes. GM1 gangliosidosis arises from a genetic deficiency of the acid b- galactosidase that catabolizes ganglioside GM1, whereas Sandhoff disease (SD) arises from genetic deficiency in the b-hexosaminidase b subunit that catabolizes ganglioside GM2. Ganglioside accumulation in these diseases leads to neuronal death, inflammation, and progressive neurological deterioration. Our studies will involve diverse and complimentary approaches for disease management. This research will evaluate NB-DGJ as a substrate reduction therapy, neural stem cells (NSCs), as a cross-correctional therapy, and caloric restriction (CR) as an anti-inflammatory therapy. NB-DGJ decreases the rate of glyco- sphingolipid (GSL) biosynthesis thereby counterbalancing an impaired rate of catabolism. NSCs provide the missing lysosomal enzyme thereby reducing GSL storage, whereas CR improves health through effects on CNS inflammatory processes. Aim 1 will determine the effects of NB-DGJ on the GSL composition of postnatal brains in normal mice and in the GM1 gangliosidosis and SD mutants. This aim will determine, a) the timing and extent of brain ganglioside recovery following NB-DGJ treatment, b) the extent to which GSL synthesis inhibition delays pathological ganglioside storage in CNS tissues, and c) whether GSL synthesis inhibition delays myelin abnormalities in the storage disease mice. Aim 2 will evaluate the therapeutic potential of neural stem cell (NSC) transplantation alone and together with NB-DGJ in developing SD mice. We hypothesize that NSCs will act synergistically with and NB-DGJ to reduce accumulating GSLs and provide maximal therapeutic effect. Aim 3 will examine the influence of NB-DGJ on embryo gangliosides following in utero administration. These studies will test the feasibility of timed drug release for in utero substrate reduction therapy for GM1 gangliosidosis. Aim 4 will test the hypothesis that CR reduces CNS inflammation and that CR and NB-DGJ act synergistically in managing CNS inflammation, ganglioside accumulation, and disease progression. The proposed studies will provide essential information on combinatorial therapies for the ganglioside storage diseases and will have translational benefit to the clinic.