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终身治疗神经节苷脂储存病的方法。神经节苷脂沉积症是一组无法治愈的神经退行性疾病，涉及神经节苷脂GM 1或GM 2在溶酶体中的储存。GM 1神经节苷脂病是由分解代谢神经节苷脂GM 1的酸性B-半乳糖苷酶的遗传缺陷引起的，而桑德霍夫病（SD）是由分解代谢神经节苷脂GM 2的b-氨基己糖苷酶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、炎症和进行性神经功能恶化。我们的研究将涉及疾病管理的多样化和互补的方法。这项研究将评估NB-DGJ作为底物减少疗法，神经干细胞（NSC）作为交叉矫正疗法，以及热量限制（CR）作为抗炎疗法。NB-DGJ降低了糖-鞘脂（GSL）生物合成的速率，从而平衡受损的催化剂速率。NSC提供缺失的溶酶体酶，从而减少GSL储存，而CR通过对CNS炎症过程的影响改善健康。目的1将确定NB-DGJ对正常小鼠和GM 1神经节苷脂沉积症和SD突变小鼠出生后脑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组织中病理性神经节苷脂蓄积的程度，和c）GSL合成抑制是否延迟蓄积病小鼠中的髓鞘异常。目的2评价神经干细胞移植及与NB-DGJ联合移植对发育期SD小鼠的治疗作用。我们假设NSC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将检查NB-DGJ在子宫内施用后对胚胎神经节苷脂的影响。这些研究将测试定时药物释放用于子宫内底物减少治疗GM 1神经节苷脂沉积症的可行性。目的4将检验CR减少CNS炎症以及CR和NB-DGJ在管理CNS炎症、神经节苷脂积累和疾病进展中协同作用的假设。这些研究将为神经节苷脂沉积病的联合治疗提供重要信息，并将对临床产生转化效益。

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.