CONNECTIVE TISSUE ACTIVATION IN RHEUMATIC DISEASES

风湿性疾病中的结缔组织激活

• 批准号: 3154726
• 负责人: C WILLIAM CASTOR
• 金额: $ 22.73万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-02-01 至 1993-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3154726
• 关键词: antirheumatic agents; chemical structure function; chemotaxis; collagenase; enzyme linked immunosorbent assay; fibroblasts; glycosylation; hormone regulation /control mechanism; human tissue; inflammation; laboratory rabbit; peptides; protein sequence; rheumatism; rheumatoid arthritis; synovial fluid; synovial membrane; synovitis; tissue /cell culture; wound healing

The key hypothesis of this proposal holds that the connective tissue activation process contributes to the events of inflammation, influencing both the reparative (proliferative) and destructive components. The long term objectives will be: 1) to define the molecular characteristics of two potent initiators of connective tissue activation, connective tissue activating peptides III and V, (CTAP-III and CTAP-V), 2) to assess the relevance of CTAP-III and CTAP-V to the inflammatory process and rheumatic diseases, and 3) to define the mechanisms by which these CTAPs initiate and sustain connective tissue activation, and to define their pathogenetic roles in inflammation. Molecular characterization of the mediators CTAP III and V will be accomplished by protein fractionation guided by relevant bioassays and detailed characterization of the amino acid sequence and carbohydrate composition of the agonists. Structural studies of CTAP-IlI will concentrate on the significance of its isoelectric point microheterogeneity and glycosylation; studies of CTAP-V will concentrate on primary structure. This is crucial to design of competitive molecules and development of additional tactics for detailed study of these agents in clinical contexts. Immunostaining procedures and computer assisted image analysis will permit localization of CTAP-III and V in normal and pathologic tissues. Immunobinding and molecular biologic studies will define local formation of these growth factors. ELISA measurements of CTAP-III and V plasma levels will be correlated with rheumatic disease activity and the efficacy of drug interventions. Development of recombinant CTAP molecules and synthetic peptide fragments of both native and novel configuration offers an opportunity to develop new tactics to influence specific key sites in the inflammatory process. It will be important to define in greater detail the mechanism of action of CTAP mediators with focus on receptor studies, chemotaxis, collagenase formation and mechanisms controlling the biosynthesis and secretion of CTAP mediators. The ultimate goal of these studies is the development of agents or procedures capable of favorably modifying the inflammatory process in man. This includes suppressing the process (as in rheumatoid arthritis), and enhancing aspects of it (as in wound healing).

该提案的关键假设认为，连接词 组织激活过程有助于以下事件 炎症，影响修复（增殖）和 破坏性成分。 长期目标是： 1）定义两种有效的分子特征 结缔组织活化引发剂、结缔组织 激活肽 III 和 V，（CTAP-III 和 CTAP-V）， 2) 评估 CTAP-III 和 CTAP-V 与 炎症过程和风湿性疾病，以及 3) 定义这些 CTAP 启动和启动的机制 维持结缔组织活化，并定义其 在炎症中的致病作用。 介体 CTAP III 和 V 的分子表征将是 通过相关生物测定指导下的蛋白质分级分离来完成 以及氨基酸序列的详细表征和 激动剂的碳水化合物组成。 结构研究 CTAP-III将重点关注其等电点的意义 点微异质性和糖基化； CTAP-V的研究将 专注于初级结构。 这对设计至关重要 竞争分子和开发额外的策略 在临床背景下对这些药物进行详细研究。 免疫染色程序和计算机辅助图像分析将 允许在正常和病理状态下定位 CTAP-III 和 V 组织。 免疫结合和分子生物学研究将定义 这些生长因子的局部形成。 ELISA 测量 CTAP-III 和 V 血浆水平与风湿病相关 疾病活动度和药物干预的功效。 重组CTAP分子和合成肽的开发 本机和新颖配置的片段提供了 有机会制定新策略来影响特定的关键站点 在炎症过程中。 更详细地定义其机制非常重要 CTAP 介质的作用，重点是受体研究， 趋化性、胶原酶形成和控制机制 CTAP 介质的生物合成和分泌。 最终目标 这些研究的重点是开发能够 有利地改变人类的炎症过程。 这 包括抑制这一过程（如类风湿性关节炎），以及 增强它的各个方面（如伤口愈合）。