Glycosaminoglycans in FGF/FGFR Signaling

FGF/FGFR 信号转导中的糖胺聚糖

基本信息

  • 批准号:
    7338368
  • 负责人:
  • 金额:
    $ 29.01万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2004
  • 资助国家:
    美国
  • 起止时间:
    2004-01-01 至 2010-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Fibroblast growth factor (FGF) signaling is contingent on the formation of a ternary complex with the FGF receptor (FGFR) and with specific structures of glycosaminoglycan (GAG) chains. Genetic defects in FGFs, FGFRs or in GAG biosynthesis have been shown to be lethal or result in overgrowth, dwarfism, and other syndromes. Animals with defects in GAG biosynthesis show a complete loss of FGF/FGFR signaling pathways. We recently discovered that chondroitin sulfate could activate FGF/FGFR signaling in a fashion similar to heparan sulfate. Both heparan sulfate and chondroitin sulfate are highly sulfated linear GAG chains abundantly expressed on the cell surface and in the extracellular matrix in the forms of heparan sulfate, chondroitin sulfate, or heparan/chondroitin sulfate hybrid proteoglycans. The FGF/FGFR/GAG interactions depend to a large extent on the specific GAG sequences. GAG sequences are not directly encoded by genes, but are put together in the Golgi by enzymes encoded by over 40 genes. This generates a huge variety of GAG sequences. The overall goal of the current grant proposal is to understand how GAGs coordinately regulate FGF/FGFR signaling at the molecular level. In the first aim, we will dissect the roles of heparan and chondroitin sulfate in FGF/FGFR signaling in a defined cellular system, The central hypothesis of this aim is that specific heparan and chondroitin sulfate sequences regulate distinct aspects of FGF/FGFR signaling. Since most animal cells make both heparan and chondroitin sulfate, our goal is to prepare a comprehensive library of CHO cell lines that express defined heparan or chondroitin sulfate sequences. This library will be a unique tool for establishing GAG structure-function relationships in FGF/FGFR signaling. In the second aim, we will clone the long sought epimerase of chondroitin sulfate biosynthesis and use it as a tool to rebuild chondroitin sulfate structures that activate FGF/FGFR signaling. In the third aim, we will determine by mass spectrometry the fine structures of GAGs in growth plates that are involved in FGF/FGFR signaling. The central hypothesis of this aim is that specific heparan and chondroitin sulfate structures function to enhance or suppress FGF signals at different biological sites within the growth plate. The goal of this aim is to discover such GAG structures. The long-term outcome of this work will contribute to a better understanding of diseases caused by disordered GAG-dependant FGF/FGFR signaling. The work may suggest novel therapeutic applications of GAG biology.
说明书(申请人提供):成纤维细胞生长因子信号转导取决于与成纤维细胞生长因子受体(FGFR)和糖胺多聚糖(GAG)链的特殊结构的三元复合体的形成。FGFs、FGFRs或GAG生物合成中的遗传缺陷已被证明是致命的,或导致过度生长、侏儒症和其他综合征。GAG生物合成缺陷的动物表现为完全丧失了成纤维细胞生长因子/FGFR信号通路。我们最近发现,硫酸软骨素能够以类似于硫酸肝素的方式激活成纤维细胞生长因子/纤维生长因子受体信号。硫酸乙酰肝素和硫酸软骨素都是高度硫酸盐化的线性GAG链,以硫酸肝素、硫酸软骨素或肝素/硫酸软骨素杂化蛋白多糖的形式在细胞表面和细胞外基质中大量表达。FGF/FGFR/GAG的相互作用在很大程度上取决于特定的GAG序列。GAG序列不是由基因直接编码的,而是由40多个基因编码的酶在高尔基体中组合在一起的。这就产生了各种各样的GAG序列。目前拨款提案的总体目标是了解GAG如何在分子水平上协调调节成纤维细胞生长因子/FGFR信号。在第一个目标中,我们将剖析肝素和硫酸软骨素在确定的细胞系统中在成纤维细胞生长因子/成纤维细胞生长因子受体信号转导中的作用,这个目标的中心假设是特定的肝素和硫酸软骨素序列调节成纤维细胞生长因子/成纤维细胞生长因子受体信号的不同方面。由于大多数动物细胞同时产生肝素和硫酸软骨素,我们的目标是准备一个完整的CHO细胞株文库,表达明确的肝素或硫酸软骨素序列。该文库将成为建立Fgf/FGFR信号中GAG结构-功能关系的独特工具。在第二个目标中,我们将克隆长期寻找的硫酸软骨素生物合成的下同聚体,并将其作为工具来重建激活成纤维细胞生长因子/成纤维细胞生长因子受体信号的硫酸软骨素结构。在第三个目标中,我们将通过质谱学来确定生长板中参与成纤维细胞生长因子/成纤维细胞生长因子受体信号转导的GAG的精细结构。这一目标的中心假设是,特定的肝素和硫酸软骨素结构在生长板内的不同生物位置起到增强或抑制成纤维细胞生长因子信号的作用。这一目标的目的是发现这种恶作剧结构。这项工作的长期成果将有助于更好地理解GAG依赖的成纤维细胞生长因子/FGFR信号通路紊乱所引起的疾病。这项工作可能会为Gag生物学提供新的治疗应用。

项目成果

期刊论文数量(11)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Identification of Chemically Sulfated/desulfated Glycosaminoglycans in Contaminated Heparins and Development of a Simple Assay for the Detection of Most Contaminants in Heparin.
污染肝素中化学硫酸化/脱硫糖胺聚糖的鉴定以及肝素中大多数污染物检测的简单测定方法的开发。
  • DOI:
  • 发表时间:
    2010
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Pan,Jing;Qian,Yi;Zhou,Xiaodong;Pazandak,Andrew;Frazier,SarahB;Weiser,Peter;Lu,Hong;Zhang,Lijuan
  • 通讯作者:
    Zhang,Lijuan
Secreted NS1 of dengue virus attaches to the surface of cells via interactions with heparan sulfate and chondroitin sulfate E.
  • DOI:
    10.1371/journal.ppat.0030183
  • 发表时间:
    2007-11
  • 期刊:
  • 影响因子:
    6.7
  • 作者:
    Avirutnan P;Zhang L;Punyadee N;Manuyakorn A;Puttikhunt C;Kasinrerk W;Malasit P;Atkinson JP;Diamond MS
  • 通讯作者:
    Diamond MS
Quantification of glycosaminoglycans by reversed-phase HPLC separation of fluorescent isoindole derivatives.
  • DOI:
    10.1093/glycob/cwj037
  • 发表时间:
    2006
  • 期刊:
  • 影响因子:
    4.3
  • 作者:
    D. Studelska;Kari Giljum;L. McDowell;Lijuan Zhang
  • 通讯作者:
    D. Studelska;Kari Giljum;L. McDowell;Lijuan Zhang
Glycosaminoglycans in Human and Bovine Serum: Detection of Twenty-Four Heparan Sulfate and Chondroitin Sulfate Motifs Including a Novel Sialic Acid-modified Chondroitin Sulfate Linkage Hexasaccharide.
  • DOI:
    10.4137/gbi.s4273
  • 发表时间:
    2010-02
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Hong Lu;L. McDowell;D. Studelska;Lijuan Zhang
  • 通讯作者:
    Hong Lu;L. McDowell;D. Studelska;Lijuan Zhang
Heparin and oversulfated heparin byproduct induce thrombin generation through contact system activation in plasma of patients with HIT.
肝素和过硫酸肝素副产物通过 HIT 患者血浆中的接触系统激活诱导凝血酶产生。
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LIJUAN ZHANG其他文献

LIJUAN ZHANG的其他文献

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{{ truncateString('LIJUAN ZHANG', 18)}}的其他基金

Glycosaminoglycans in FGF/FGFR Signaling.
FGF/FGFR 信号转导中的糖胺聚糖。
  • 批准号:
    6999334
  • 财政年份:
    2004
  • 资助金额:
    $ 29.01万
  • 项目类别:
Glycosaminoglycans in FGF/FGFR Signaling
FGF/FGFR 信号转导中的糖胺聚糖
  • 批准号:
    7159333
  • 财政年份:
    2004
  • 资助金额:
    $ 29.01万
  • 项目类别:
Glycosaminoglycans in FGF/FGFR Signaling.
FGF/FGFR 信号转导中的糖胺聚糖。
  • 批准号:
    6837149
  • 财政年份:
    2004
  • 资助金额:
    $ 29.01万
  • 项目类别:
Glycosaminoglycans in FGF/FGFR Signaling
FGF/FGFR 信号转导中的糖胺聚糖
  • 批准号:
    6712655
  • 财政年份:
    2004
  • 资助金额:
    $ 29.01万
  • 项目类别:
PRECURSOR FORMATION OF ANTICOAGULANT HEPARAN SULFATE
抗凝剂硫酸乙酰肝素的前体形成
  • 批准号:
    2420692
  • 财政年份:
    1998
  • 资助金额:
    $ 29.01万
  • 项目类别:
PRECURSOR FORMATION OF ANTICOAGULANT HEPARAN SULFATE
抗凝剂硫酸乙酰肝素的前体形成
  • 批准号:
    2771218
  • 财政年份:
    1998
  • 资助金额:
    $ 29.01万
  • 项目类别:

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