CATABOLISM OF COAGULATION FACTOR VIII
凝血因子 VIII 的分解代谢
基本信息
- 批准号:6702276
- 负责人:
- 金额:$ 0.48万
- 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 2004-06-30
- 项目状态:已结题
- 来源:
- 关键词:aminoacidbinding sitesbioengineering /biomedical engineeringbiotransformationblood disorderblood disorder chemotherapyclearance ratecoagulation factor VIIIdisease /disorder modeldrug metabolismgene expressiongenetic manipulationhemophilia Asheparinintermolecular interactionlaboratory mouselow density lipoprotein receptormutantprotein protein interactionprotein structure functionproteoglycanreceptor bindingrecombinant proteinstissue /cell culturevon 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)是一个重要的
项目成果
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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:
$ 0.48万 - 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:
$ 0.48万 - 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:
$ 0.48万 - 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:
$ 0.48万 - 项目类别:
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