STRUCTURE-FUNCTION RELATIONSHIPS OF LYSOSOMAL ENZYMES
STRUCTURE-FUNCTION RELATIONSHIPS OF LYSOSOMAL ENZYMES
批准号:
5202032
负责人:
R L PROIA
金额:
$0.0万
依托单位国家:
美国
项目类别:
财政年份:
--
资助国家:
美国
项目状态:
未结题
起止时间:
至
关键词:
Sandhoff disease Tay Sachs disease beta N acetylhexosaminidase cerebellar Purkinje cell disease /disorder model embryonic stem cell enzyme deficiency enzyme structure gene targeting genetically modified animals laboratory mouse model design /development motor neurons phenotype protein structure function
中文摘要
Tay-Sachs和Sandhoff病是严重的神经退行性疾病
其特征在于作为结果受损的GM 2神经节苷脂降解
β-氨基己糖苷酶A缺乏症 HEXA和HEXB突变
编码β-氨基己糖苷酶A亚基的基因导致Tay-
萨克斯和山德霍夫病。 在人类中,
两种疾病的表型和神经病理学非常相似。
通过破坏胚胎干细胞中的Hexa和Hexb基因,
我们建立了相应的Tay-Sachs和Sandhoff小鼠模型
疾病 破坏的Hexa或Hexb基因纯合子小鼠
缺乏β-氨基己糖苷酶A,
大脑 然而,与Tay-Sachs和Sandhoff病患者不同,
Hexa和Hexb“敲除”小鼠显示出非常不同的表型。 的
Hexa基因敲除小鼠的寿命正常(约2年),
神经系统异常 相比之下,Hexb基因敲除小鼠
严重影响。 从大约3.5个月开始,这些动物表现出
进行性步态异常、肌肉萎缩和痉挛。 了5
几个月后,这些动物几乎完全瘫痪。 一致
与不同表型相关的是,
两种突变小鼠的储存神经元。 在Hexb淘汰赛中
在小鼠中枢神经系统的几乎所有神经元中观察到储存
系统 相反,在Hexa基因敲除小鼠中,
大脑的某些区域。 根据表型差异,
值得注意的是,小脑浦肯野区存在显著的储存,
细胞和脊髓运动神经元中的Hexb,但不是Hexa
基因敲除小鼠 此外,我们还发现,
两种小鼠模型之间的差异是由于
神经节苷脂降解途径之间的小鼠和人类。
英文摘要
Tay-Sachs and Sandhoff diseases are severe neurodegenerative disorders
characterized by impaired GM2 ganglioside degradation as a consequence
of beta-hexosaminidase A deficiency. Mutations in the HEXA and HEXB
genes, which encode the subunits of beta-hexosaminidase A, cause Tay-
Sachs and Sandhoff disease, respectively. In humans, the neurologic
phenotype and neuropathology in the two diseases are very similar.
Through disruption of the Hexa and Hexb genes in embryonic stem cells,
we have established mouse models corresponding to Tay-Sachs and Sandhoff
diseases. Mice homozygous for either the disrupted Hexa or Hexb gene
were deficient in beta-hexosaminidase A and accumulated GM2 in their
brains. However, unlike Tay-Sachs and Sandhoff disease patients, the
Hexa and Hexb "knock-out" mice displayed very different phenotypes. The
Hexa knock-out mice had a normal life span (about 2 years) and showed no
neurologic abnormalities. In contrast, the Hexb knock-out mice were
severely affected. Beginning at about 3.5 months these animals showed
progressive gait abnormalities, muscle wasting and spasticity. By 5
months the animals displayed nearly complete limb paralysis. Consistent
with the different phenotypes were athe number and distribution of
storage neurons in the two types of mutant mice. In the Hexb knock-out
mice storage was observed in almost all neurons in the central nervous
system. In contrast, in the Hexa knock-out mice storage was restricted
to certain regions of the brain. In light of the phenotypic difference,
it is notable the significant storage was found in cerebellar Purkinje
cells and in the spinal cord motor neurons in the Hexb but not the Hexa
knock-out mice. Furthermore, we have found that phenotypic difference
between the two mouse models is the result of differences in the
ganglioside degradation pathway between mice and humans.
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STRUCTURE-FUNCTION RELATIONSHIPS OF LYSOSOMAL ENZYMES
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批准号:6105753
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STRUCTURE-FUNCTION RELATIONSHIPS OF LYSOSOMAL ENZYMES
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批准号:3840463
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STRUCTURE-FUNCTION RELATIONSHIPS OF LYSOSOMAL ENZYMES
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批准号:3855397
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STRUCTURE-FUNCTION RELATIONSHIPS OF LYSOSOMAL ENZYMES
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批准号:3964812
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STRUCTURE-FUNCTION RELATIONSHIPS OF LYSOSOMAL ENZYMES
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批准号:3776923
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STRUCTURE-FUNCTION RELATIONSHIPS OF LYSOSOMAL ENZYMES
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批准号:3876427
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STRUCTURE-FUNCTION RELATIONSHIPS OF LYSOSOMAL ENZYMES
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批准号:6162011
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STRUCTURE-FUNCTION RELATIONSHIPS OF LYSOSOMAL ENZYMES
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批准号:3941096
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STRUCTURE-FUNCTION RELATIONSHIPS OF LYSOSOMAL ENZYMES
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STRUCTURE-FUNCTION RELATIONSHIPS OF LYSOSOMAL ENZYMES
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批准号:3918242
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STRUCTURE-FUNCTION RELATIONSHIPS OF LYSOSOMAL ENZYMES
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批准号:3754841
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STRUCTURE-FUNCTION RELATIONSHIPS OF LYSOSOMAL ENZYMES
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批准号:2573656
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