CATABOLISM OF COAGULATION FACTOR VIII
凝血因子 VIII 的分解代谢
基本信息
- 批准号:6629143
- 负责人:
- 金额:$ 30.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2001
- 资助国家:美国
- 起止时间:2001-02-01 至 2005-01-31
- 项目状态:已结题
- 来源:
- 关键词:aminoacid binding sites bioengineering /biomedical engineering biotransformation blood disorder blood disorder chemotherapy clearance rate coagulation factor VIII disease /disorder model drug metabolism gene expression genetic manipulation hemophilia As heparin intermolecular interaction laboratory mouse low density lipoprotein receptor mutant protein protein interaction protein structure function proteoglycan receptor binding recombinant proteins tissue /cell culture von Willebrand factor
项目摘要
DESCRIPTION: (Investigator's abstract) Factor VIII (fVIII) is an important
plasma component required for haemostasis, since genetic defects in this
molecule cause a life-threatening coagulation disorder known as Hemophilia A.
This genetic disease is treated by repeated infusions of expensive fVIII
products. A more effective therapy can be provided if the molecular basis of
fVIII clearance is understood and a novel recombinant fVIII protein with a
prolonged lifetime in circulation is developed. We have previously found that
the low density lipoprotein receptor-related protein (LRP), the main endocytic
liver receptor, and cell surface heparan sulfate proteoglycans (HSPGs)
cooperate in the clearance of fVIII, since simultaneous blocking of these two
receptor systems dramatically prolonged the lifetime of fVIII in mice. While in
purified system both LRP and HSPGs were shown to interact with fVIII via the
sites located within the A2 domain, the precise molecular events responsible
for fVIII catabolism are currently not well characterized. We propose to
identify the amino acid residues critical for fVIII interaction with LRP and
HSPGs by mutational analysis of the regions previously identified as LRP and
HSPGs binding sites of fVIII. The mutations will be introduced into B-domain
depleted recombinant fVIII, which is functionally identical to plasma-derived
fVIII and is presently used for Hemophilia A therapy. We will express these
fVIII mutants in mammalian cells and test them for binding to LRP and heparin,
used as model of HSPGs, in purified systems. The catabolism of the mutants will
be examined in vitro using LRP-expressing cells and in vivo in a murine model
of Hemophilia A. These experiments will identify fVIII mutants with reduced
binding to LRP and HSPGs and will clarify the role of these two receptor
systems in fVIIII clearance. The proposed studies should develop an insight
into the mechanism of fVIII regulation in circulation and will provide a basis
for generation of a novel type of recombinant fVIII products, having a
prolonged lifetime in circulation. Development of such fVIII derivatives, which
may be prospective for less expensive Hemophilia A therapy, is the long-term
goal of our studies.
描述:(研究者摘要)因子VIII(fVIII)是一种重要的
止血所需的血浆成分,因为这种基因缺陷,
这种分子会导致一种危及生命的凝血障碍,即血友病A。
这种遗传性疾病的治疗方法是反复注射昂贵的凝血因子VIII
产品.如果能够从分子水平上研究肿瘤的分子基础,
了解了fVIII清除,并发现了一种新的具有
延长了循环寿命。我们先前发现,
低密度脂蛋白受体相关蛋白(LRP),主要的内吞
肝受体和细胞表面硫酸乙酰肝素蛋白聚糖(HSPGs)
合作清除fVIII,因为同时阻断这两个
受体系统显著延长了小鼠中FVIII的寿命。而在
纯化的系统LRP和HSPG都显示出通过
位于A2结构域内的位点,
对于FVIII catastrophic目前没有很好地表征。我们建议
鉴定对FVIII与LRP相互作用至关重要的氨基酸残基,
通过对先前鉴定为LRP的区域的突变分析,
fVIII的HSPG结合位点。突变将被引入B结构域
耗尽的重组fVIII,其功能上与血浆来源的
FVIII,目前用于血友病A治疗。我们将表达这些
在哺乳动物细胞中的FVIII突变体,并测试它们与LRP和肝素的结合,
在纯化系统中用作HSPG的模型。变种人的大屠杀
使用LRP表达细胞在体外和在鼠模型中在体内进行检查
血友病A这些实验将鉴定具有降低的
结合LRP和HSPGs,并将阐明这两种受体的作用
fVIII-R系统。拟议中的研究应有助于深入了解
进入流通中的FVIII调节机制,并将提供基础
用于产生新型重组FVIII产物,其具有
延长循环寿命。开发这种FVIII衍生物,
可能是前瞻性的便宜血友病A治疗,是长期的
我们学习的目标。
项目成果
期刊论文数量(0)
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EVGUENI L. SAENKO其他文献
EVGUENI L. SAENKO的其他文献
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{{ truncateString('EVGUENI L. SAENKO', 18)}}的其他基金
Prolongation of Factor VIII Lifetime in Circulation
延长因子 VIII 在循环中的寿命
- 批准号:
6900877 - 财政年份:2003
- 资助金额:
$ 30.84万 - 项目类别:
Prolongation of Factor VIII Lifetime in Circulation
延长因子 VIII 在循环中的寿命
- 批准号:
6742426 - 财政年份:2003
- 资助金额:
$ 30.84万 - 项目类别:
Prolongation of Factor VIII Lifetime in Circulation
延长因子 VIII 在循环中的寿命
- 批准号:
6597896 - 财政年份:2003
- 资助金额:
$ 30.84万 - 项目类别:
Prolongation of Factor VIII Lifetime in Circulation
延长因子 VIII 在循环中的寿命
- 批准号:
6881127 - 财政年份:2003
- 资助金额:
$ 30.84万 - 项目类别:
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