Canavan Disease: Pathogenesis and Treatment
卡纳万病:发病机制和治疗
基本信息
- 批准号:7656990
- 负责人:
- 金额:$ 3.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1999
- 资助国家:美国
- 起止时间:1999-12-01 至 2009-05-31
- 项目状态:已结题
- 来源:
- 关键词:AcetatesAcetyl Coenzyme AAffectAgeAmino AcidsAspartoacylaseBrainCanavan DiseaseChildChronicCodeDeacetylationDevelopmentEnzymesGenesGoalsHourKnowledgeLeadLipidsMethodsModelingMusMutationMyelinN-acetylaspartateNervous system structureNeurodegenerative DisordersNumbersOligodendrogliaOral AdministrationPathogenesisPathologyPathway interactionsPrion DiseasesRoleSupplementationTestingTherapeuticThinkingTissuesfollow-up
项目摘要
Canavan disease (CD) is an autosom al-recessive neurodegenerative disorder caused by mutations in the
gene coding for the enzyme aspartoacylase (ASPA). ASPA catalyzes deacetylation of N-acetylaspartate
(NAA), an abundant (~ 10 mM) and nervous system-specific amino acid derivative. CD is characterized by
spongiform degeneration of the brain resulting in severe psychomotor retardation, with most affected
children dying before the age of 10. The precise pathogenesis of CD remains unclear. The central
hypothesis is that ASPA activity is required for myelin synthesis via liberating the NAA-derived acetate for
the synthesis of acetyl CoA, which is used in the synthesis of the lipid portion of myelin. In this hypothesis,
CD is thought to result from defective myelin synthesis caused by a deficiency in the supply of the NAAderived
acetate. A number of studies, including our recent demonstration of the selective localization of
ASPA in oligodendrocytes in the CNS, are consistent with the acetate deficiency hypothesis of CD.
Furthermore, we have recently tested the acetate deficiency hypothesis in the murine model of CD (ASPA -/-
) directly by 1) determining acetate levels in the brain and 2) studying the myelin-associated lipid synthesis.
The results showed that in CD mice brain acetate levels decreased by about 80% and synthesis of a number
of myelin related lipids also decreased significantly. These results provided the first direct evidence in
support of this hypothesis. A major implication of these findings is that acetate supplementation is likely to
provide a simple and inexpensive therapeutic approach for CD. Toward this goal, we have made progress by
finding that oral administration of glyceryl triacetate (Triacetin), an acetate precursor, caused acetate levels
in the brain to increase by about 10- fold in 1-2 hours, and efforts to test whether or not acetate
supplementation using glyceryl triacetate is effective as a treatment of CD is in progress. The Central
hypothesis of this competitive renewal application remains the same as that of the previous application.
This application involves additional specific aims focused on continuing our efforts toward acetate
supplementation therapy for CD and testing additional aspects of CD pathogenesis as a follow up to the
current findings. The immediate goals are 1) to continue our ongoing efforts to correct the acetate
deficiency of CD using chronic GT A administration and to test its effect on the development of CD, 2) to
characterize the acetate pathway of myelin lipid synthesis to further understand the functional roles of NAA
and 3) to determine the CNS tissue compartments in which NAA is increased in CD as a first step to
understand the role of increased NAA in CD pathology. These studies are likely to lead to a simple and
inexpensive method for the treatment of CD and also advance our knowledge on the functional roles of NAA
and the relationship of increased NAA to CD pathology.
Canavan病(CD)是一种常染色体隐性遗传性神经退行性疾病,由基因突变引起
天冬氨酸氨基转移酶(ASPA)基因编码。ASPA催化N-乙酰天冬氨酸脱乙酰化
(NAA),一种丰富的(~10 mM)神经系统特异性氨基酸衍生物。CD的特点是
大脑海绵状变性导致严重的精神运动迟缓,影响最大
儿童在10岁之前死亡。CD的确切发病机制尚不清楚。中环
假设ASPA活性是髓鞘合成所必需的,是通过释放NAA衍生的醋酸酯来实现的。
乙酰辅酶A的合成,用于合成髓磷脂的脂部分。在这个假设中,
CD被认为是由于NAA来源的供应不足导致的髓鞘合成缺陷所致
醋酸盐。一些研究,包括我们最近演示的选择性本地化
中枢神经内少突胶质细胞中的ASPA,与Cd的醋酸盐缺乏假说一致。
此外,我们最近在CD(ASPA-/-)小鼠模型中测试了醋酸盐缺乏假说
)直接通过1)测定大脑中的醋酸盐水平和2)研究髓鞘相关的脂质合成。
结果表明,在CD小鼠中,脑醋酸盐水平下降了约80%,并合成了一些
髓鞘相关脂类的比例也明显下降。这些结果提供了第一个直接的证据
支持这一假设。这些发现的一个主要含义是,补充醋酸盐很可能会
为CD提供了一种简单、廉价的治疗方法。为了实现这一目标,我们取得了以下进展
研究发现,口服三醋酸甘油酯(三醋酸甘油酯),一种醋酸盐前体,导致醋酸盐水平
在大脑中增加了大约10倍,在1-2小时内,努力测试是否有醋酸盐
补充使用三醋酸甘油酯是有效的,因为CD的治疗正在进行中。中环
本次竞争性续签申请的假设与上一次申请相同。
这项申请涉及额外的具体目标,重点是继续努力实现乙酸乙酯
CD的补充治疗,并测试CD发病机制的其他方面作为对CD的随访
目前的发现。目前的目标是1)继续我们正在进行的纠正醋酸盐的努力
慢性应用GTA治疗镉缺乏及其对镉发育的影响,2)
鉴定髓鞘脂肪合成的醋酸酯途径以进一步了解NAA的功能作用
3)作为第一步,确定CD中NAA增加的中枢神经系统组织区块
了解NAA升高在CD病理中的作用。这些研究可能会导致一种简单和
治疗CD的廉价方法,也促进了我们对NAA功能作用的了解
NAA升高与CD病理的关系。
项目成果
期刊论文数量(0)
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ARYAN Mangalam NAMBOODIRI其他文献
ARYAN Mangalam NAMBOODIRI的其他文献
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{{ truncateString('ARYAN Mangalam NAMBOODIRI', 18)}}的其他基金
Acetate Supplementation as a therapeutic strategy for Canavan disease
补充乙酸作为卡纳万病的治疗策略
- 批准号:
8803820 - 财政年份:2014
- 资助金额:
$ 3.8万 - 项目类别:
Acetate Supplementation as a therapeutic strategy for Canavan disease
补充乙酸作为卡纳万病的治疗策略
- 批准号:
8700038 - 财政年份:2014
- 资助金额:
$ 3.8万 - 项目类别:
Intranasal CNS delivery of drugs against organophosphorous threat agents
鼻内中枢神经系统输送针对有机磷威胁物质的药物
- 批准号:
8417465 - 财政年份:2012
- 资助金额:
$ 3.8万 - 项目类别:
Intranasal CNS delivery of drugs against organophosphorous threat agents
鼻内中枢神经系统输送针对有机磷威胁物质的药物
- 批准号:
8551756 - 财政年份:2012
- 资助金额:
$ 3.8万 - 项目类别:
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