Glycosphingolipids in Murine Neurodegenerative Diseases

小鼠神经退行性疾病中的鞘糖脂

• 批准号: 8550181
• 负责人: THOMAS N SEYFRIED
• 金额: $ 34.65万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8550181
• 关键词: Acids; Active Biological Transport; Adult Sandhoff Disease; Anabolism; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; Caloric Restriction; Carbohydrates; Carbon; Catabolism; Dependovirus; Deterioration; Diet; Diffusion; Disease; Disease Management; Encephalitis; Enzymes; Fatty acid glycerol esters; Funding; G(M2) Ganglioside; Galactosidase; Ganglioside GM1; Gangliosides; Gangliosidoses; Gangliosidosis GM1; Genes; Genetic; Glycosphingolipids; Goals; Hexosaminidases; Human; Inborn Errors of Metabolism; Infant; Inflammation; Injection of therapeutic agent; Knock-out; Length; Life; Lipids; Lysosomes; Mediating; Milk; Modification; Mothers; Multi-Drug Resistance; Mus; Myelin; Neonatal; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Optic Nerve; P-Glycoprotein; Pathology; Patients; Peritoneal; Phospholipids; Research; Retina; Role; Sandhoff Disease; System; Therapeutic; Time; Treatment Efficacy; analog; beta-n-acetylhexosaminidase; bis(monoacylglyceryl)phosphate; carbon compound; carrier mediated transport; effective therapy; gene therapy; human disease; improved; in vivo; inhibitor/antagonist; insight; ketogenic diet; ketogentic; mouse model; neurochemistry; novel; novel therapeutics; passive transport; sugar; treatment strategy; uptake

DESCRIPTION (provided by applicant): The research goal is to develop an effective life-long therapy for ganglioside storage diseases. The gangliosidoses are a group of incurable autosomal recessive inborn errors of metabolism involving storage of either ganglioside GM1 or GM2 in CNS lysosomes. Accumulation of GM1 or GM2 causes wide spread inflammation and neurodegeneration. GM1 gangliosidosis arises from a genetic deficiency of the acid ¿-galactosidase that catabolizes ganglioside GM1, whereas Sandhoff disease (SD) arises from genetic deficiency in the ¿-hexosaminidase ¿ subunit that catabolizes ganglioside GM2. Our studies will involve diverse and complimentary approaches for disease management primarily involving substrate reduction therapy and gene therapy. The studies will be largely conducted in ¿-gal -/-, and Hex¿ -/- mice that accumulate GM1 and GM2, respectively. Inhibited synthesis counterbalances impaired rate of catabolism and is referred to as substrate reduction therapy. The imino sugars, NB-DNJ, and NB-DGJ, as well as the novel PDMP analogue "3h" inhibit the rate of glycosphingolipid (GSL) biosynthesis. Our recent findings show that CNS delivery and therapeutic efficacy of NB-DNJ is significantly increased when the inhibitor is administered together with the restricted high-fat, low carbohydrate ketogenic diet (KD-R). Adeno-Associated Virus (AAV) gene therapy provides the missing lysosomal enzyme thereby reducing GSL storage throughout the CNS. The proposed studies will be an extension of those conducted over the previous funding period and will involve the following specific aims. Aim 1 will examine active and passive transport mechanisms by which the restricted ketogenic diet (KD-R) facilitates brain delivery of imino sugar and 3h to the CNS. Aim 2 will determine the degree to which the ketogenic diet can facilitate delivery of imino sugar and 3h to neonatal mouse brain through the dam's milk. Aim 3 will evaluate the degree to which AAV gene therapy corrects lipid abnormalities and inflammation in purified myelin, optic nerve, and retina in storage disease mice. Our preliminary studies show for the first time elevated levels of the unusual phospholipid, bis(monoacylglycerol)phosphate in the brains of human SD and in the ¿-gal -/-, and Hex¿ -/- mice. This lipid will be used as a novel biomarker for correction of ganglioside storage and brain inflammation. The proposed research will provide insight on novel therapeutic strategies for managing human ganglioside storage diseases.

描述（由申请人提供）：研究目标是开发一种有效的神经节苷脂储存病的终身治疗方法。神经节苷脂沉积症是一组无法治愈的常染色体隐性遗传性代谢缺陷，涉及神经节苷脂GM 1或GM 2在CNS溶酶体中的储存。GM 1或GM 2的积累引起广泛的炎症和神经变性。GM 1神经节苷脂病是由分解代谢神经节苷脂GM 1的酸性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的氨基己糖苷酶亚单位的遗传缺陷引起的。我们的研究将涉及疾病管理的多样化和互补的方法，主要涉及底物减少疗法和基因疗法。这些研究将主要在分别积累GM 1和GM 2的<$-gal -/-和Hex <$-/-小鼠中进行。抑制合成平衡受损的催化剂速率，被称为底物减少疗法。亚氨基糖、NB-DNJ和NB-DGJ以及新的PdR类似物“3 h”抑制鞘糖脂（GSL）生物合成的速率。我们最近的研究结果表明，当抑制剂与限制性高脂肪、低碳水化合物生酮饮食（KD-R）一起施用时，NB-DNJ的CNS递送和治疗功效显著增加。腺相关病毒（AAV）基因治疗提供了缺失的溶酶体酶，从而减少了整个CNS的GSL储存。建议的研究将是上一个资助期内进行的研究的延续，并会涉及以下特定目的。目的1将研究限制生酮饮食（KD-R）促进脑内亚氨基糖和3 h向中枢神经系统转运的主动和被动转运机制。目的2将确定生酮饮食可促进通过母鼠乳汁向新生小鼠脑递送亚氨基糖和3 h的程度。目的3将评估AAV基因治疗在何种程度上纠正脂质异常和炎症纯化髓鞘，视神经和视网膜在存储疾病小鼠。我们的初步研究首次表明，SD人类以及½-gal -/-和Hex ½-/-小鼠的大脑中不寻常的磷脂、双（单酰甘油）磷酸盐水平升高。这种脂质将被用作一种新的生物标志物，用于纠正神经节苷脂储存和脑炎症。拟议的研究将为管理人类神经节苷脂储存疾病的新治疗策略提供见解。