STRUCTURE-FUNCTION RELATIONSHIPS OF LYSOSOMAL ENZYMES
溶酶体酶的结构-功能关系
基本信息
- 批准号:6105753
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:Sandhoff disease Tay Sachs disease beta N acetylhexosaminidase disease /disorder model enzyme deficiency enzyme mechanism enzyme structure gangliosides gangliosidosis gene targeting genetically modified animals laboratory mouse model design /development motor neurons mucopolysaccharidosis protein degradation protein structure function
项目摘要
The sphingolipidoses are a group of severe disorders
caused by inherited defects in the degradation of sphingolipids. In
order to study pathogenesis and new treatment approaches we
developed models of some of these disorders by total gene
knockout technology in the mouse. We have applied this
technology to establish models of Tay-Sachs, Sandhoff disease and
the GM2 activator deficiency. In some of sphingolipidoses, such as
Gaucher disease, effective modeling in the mouse requires the
introduction of subtle mutational changes. Gaucher disease is
caused by mutations in the gene encoding the lysosomal enzyme
glucocerebrosidase (GC). Three clinical types of Gaucher disease
have been defined according to the presence (type 2 and 3) or
absence (type 1) of central nervous system disease and severity of
clinical manifestations. The clinical course of the disease correlates
with the type of mutation carried by the GC gene. In order to
produce mice with point mutations that correspond to the clinical
types of Gaucher disease, we have devised a highly efficient
one-step mutagenesis method -- the Single Insertion Mutagenesis
Procedure (SIMP) -- to insert human disease mutations into the
mouse GC gene. Using SIMP, mice have been generated carrying
either the very severe RecNciI mutation that can cause type 2
disease or the less severe L444P mutation associated with type 3
disease. Mice homozygous for the RecNciI mutation had little GC
enzyme activity and accumulated glucosylceramide in brain and
liver. In contrast, the mice homozygous for the L444P mutation had
higher levels of GC activity and no detectable accumulation of
glucosylceramide in brain and liver. Both the type 2 and 3 mice died
within 48 hrs of birth of a compromised epidermal permeability
barrier caused by defective glucosylceramide metabolism in the
epidermis. Current work is aimed at introducing genetic
modifications that will allow the Gaucher mice to survive past the
neonatal period.
鞘磷脂沉积症是一组严重的疾病
由鞘脂降解过程中的遗传缺陷引起。在……里面
为了研究发病机制和新的治疗方法
用全基因建立了其中一些疾病的模型
鼠标中的基因敲除技术。我们已经应用了这一点
建立泰-萨克斯、桑德霍夫病和
GM2激活剂缺乏。在一些鞘脂肪病中,例如
高谢病,在小鼠身上有效的建模需要
引入了微妙的突变变化。高谢病是
由编码溶酶体酶的基因突变引起
葡萄糖脑苷酶(GC)。高谢病的三种临床类型
已根据存在(类型2和类型3)定义,或
无中枢神经系统疾病(类型1)和严重程度
临床表现。该病的临床病程与
与GC基因携带的突变类型有关。为了
产生与临床相对应的点突变的小鼠
针对各种类型的高谢病,我们设计出了一种高效的
一步诱变法--单插入诱变法
程序(SIMP)-将人类疾病突变插入到
小鼠GC基因。使用SIMP,已经产生了携带有
要么是可以导致2型的非常严重的RecNciI突变
与3型相关的疾病或不太严重的L444P突变
疾病。携带RecNciI突变纯合子的小鼠几乎没有GC
脑组织中酶活性和葡萄糖神经酰胺蓄积量
肝脏。相比之下,L444P突变纯合的小鼠有
较高水平的GC活性和未检测到的
大脑和肝脏中的葡萄糖神经酰胺。2型和3型小鼠均死亡
出生后48小时内表皮渗透性受损
葡萄糖神经酰胺代谢缺陷引起的脑血管屏障
表皮。目前的工作旨在引入基因
将允许高雪鼠存活过
新生儿期。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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