REGULATION OF AGGRECAN CATABOLISM
聚集蛋白分解代谢的调节
基本信息
- 批准号:6364583
- 负责人:
- 金额:$ 29.28万
- 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:2001-08-01 至 2006-05-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): Aggrecan is a large hybrid proteoglycan of
the cartilage extracellular matrix, which is critical to cartilage functional
properties. The interglobular domain (IGD) in mammalian aggrecan contains
aggrecanase and matrix metalloproteinase cleavage sites, and additional sites
for aggrecanase-mediated cleavage have been described in the CS-2 domain. We
have constructed the first full-sized aggrecan expression vector to surmount
the limitations of smaller aggrecan subdomain constructs used previously as
mutagenizable aggrecanase substrates. We propose the hypothesis that highly
conserved proteinase cleavage sites in aggrecan are important in regulation of
aggrecan turnover. We further hypothesize that the chondrocyte can regulate
aggrecan catabolism by altering glycosylation patterns on the aggrecan
substrate. To address these hypotheses, we propose the following Specific Aims:
Specific Aim 1: To determine amino acid residues required for recognition and
cleavage by aggrecanase. Comparison of known aggrecanase cleavage sites in
aggrecan and brevican have revealed conservation of clusters of flanking
residues. We will establish whether these flanking residues are required for
cleavage by aggrecanase by replacing conserved residues and assaying for
cleavage at each site. Specific Aim 2: To determine the functional
relationships between cleavage sites in aggrecan. Cleavage at the MMP site in
the IGD has been shown to inhibit aggrecanase cleavage within the IGD,
suggesting the involvement of motifs in the G1 domain in aggrecanase substrate
recognition. We will mutagenize these G1 motifs and assay for aggrecanase
cleavage at the IGD site. There is also evidence that cleavage of aggrecan
C-terminal sites precedes, and may be a prerequisite for cleavage within the
IGD. We will mutagenize aggrecanase sites within the CS-2 domain and determine
directly whether cleavage at the IGD is inhibited. Specific Aim 3: To determine
whether susceptibility to aggrecanase cleavage may be regulated by known and
potential sites for KS substitution of aggrecan. We will determine the optimal
cell type for expression of KS-containing aggrecan. We will mutagenize
threonine residues in the IGD and "nodal" region of the CS-2 domain to prevent
KS substitution and assay for aggrecanase susceptibility. Wild-type and mutant
aggrecan constructs will be expressed in chondrocytes isolated from cartilage
of different aged animals, to determine if there is an age-specific pattern of
glycosylation that influences aggrecanase susceptibility.
描述(由申请人提供):聚合蛋白是一种大型杂交蛋白多糖
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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THOMAS Martin HERING其他文献
THOMAS Martin HERING的其他文献
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{{ truncateString('THOMAS Martin HERING', 18)}}的其他基金
Zfp28 and Mesenchymal Stem Cell Differentiation
Zfp28 和间充质干细胞分化
- 批准号:
7232460 - 财政年份:2006
- 资助金额:
$ 29.28万 - 项目类别:
Zfp28 and Mesenchymal Stem Cell Differentiation
Zfp28 和间充质干细胞分化
- 批准号:
7095408 - 财政年份:2006
- 资助金额:
$ 29.28万 - 项目类别:
TRANSCRIPTIONAL CONTROL OF CHONDROGENIC DIFFERENTIATION
软骨分化的转录控制
- 批准号:
6171519 - 财政年份:1999
- 资助金额:
$ 29.28万 - 项目类别:
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