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CONNECTIVE TISSUE ACTIVATION IN RHEUMATIC DISEASES

风湿性疾病中的结缔组织激活

基本信息

批准号：
2732809
负责人：
C WILLIAM CASTOR
金额：
$ 25.97万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
1978
资助国家：
美国
起止时间：
1978-02-01 至 2000-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2732809
关键词：
X ray crystallography chemical structure function connective tissue connective tissue pharmacology cytokine cytokine receptors fibroblasts human tissue inflammation laboratory rabbit nuclear magnetic resonance spectroscopy osteoarthritis peptide chemical synthesis rheumatoid arthritis synovial membrane synthetic peptide tissue /cell culture wound healing

项目摘要

The key hypothesis of this proposal holds that the connective tissue activation process, mediated by potent cytokines drives many of the events of inflammation, influencing both reparative (proliferative) and destructive mechanisms. We propose to define the manner in which the cytokine, CTAP-III, initiates and sustains connective tissue activation, and to define its pathogenetic roles in inflammation. Construction of recombinant CTAP-III molecules and synthetic peptides of both native and novel configuration offers opportunities to develop new tactics to influence key sites in the inflammatory process. Our ultimate goal is to devise agents or procedures which favorably modify inflammation in man, including suppressing the process (as in rheumatoid arthritis), and enhancing aspects of normal physiology (as in wound healing). Knowledge of the structure of connective tissue activating peptide-III (CTAP-III) is critical to understanding structure-function relationships through which this cytokine expresses its biological effects. To delineate CTAP-III structure-function relationships, we will determine the residues or sequences critical to the anabolic, chemotactic and other activities in normal, OA and rheumatoid synovial cell cultures. This will be accomplished: (1) by chemical modifications of CTAP-III, (2) by construction of relevant synthetic peptides, and (3) by site directed mutagenesis of recombinant CTAP-III. The direct structure-function studies will be extended by collaborative efforts to define the three dimensional structure of CTAP-III by X-ray crystallographic and Nuclear Magnetic Resonance studies. The mechanisms/s by which CTAP-III activates connective tissue cells will be clarified by receptor binding studies and definition of possible co- ligands critical to CTAP-III dependent connective cell activation. The roles of (1) CTAP-III binding to proteoglycans of cell membranes and extracellular matrix and putative heparanase activity, and (2) CTAP-III induction of cytokines in sustaining the activated state of normal, OA, and RA synovial cells will be studied to clarify the biologic basis of chronic inflammation.

这一建议的关键假设认为，结缔组织由强效细胞因子介导的激活过程驱动许多事件炎症，影响修复（增殖）和破坏机制。我们建议界定细胞因子CTAP-III启动并维持结缔组织活化，并确定其在炎症中的致病作用。建设重组CTAP-III分子和天然和合成肽新的配置提供了开发新战术的机会，影响炎症过程中的关键部位。我们的最终目标是设计有利地改变人类炎症的试剂或程序，包括抑制该过程（如类风湿性关节炎），增强正常生理学方面（如伤口愈合）。结缔组织激活肽-III的结构知识（CTAP-III）对于理解结构-功能关系至关重要通过这些细胞因子表达其生物学效应。到描述CTAP-III结构-功能关系，我们将确定对合成代谢、趋化性和其他生物活性至关重要的残基或序列。在正常、OA和类风湿性滑膜细胞培养物中的活性。这将实现：（1）通过CTAP-III的化学修饰，（2）通过相关合成肽的构建，和（3）通过定点重组CTAP-III的诱变。直接结构-功能研究将通过合作努力来扩展，以确定三个通过X射线晶体学和核分析确定CTAP-Ⅲ的三维结构磁共振研究。 CTAP-III激活结缔组织细胞的机制将通过受体结合研究和可能的共- CTAP-III依赖性结缔细胞活化的关键配体。的（1）CTAP-III与细胞膜的蛋白聚糖结合的作用，细胞外基质和推定的乙酰肝素酶活性，和（2）CTAP-III 诱导细胞因子维持正常，OA，和RA滑膜细胞将进行研究，以阐明慢性炎症。