PATHOBIOLOGY OF MACROPHAGE-FIBRONECTIN INTERACTIONS

巨噬细胞-纤连蛋白相互作用的病理学

• 批准号: 3291331
• 负责人: LIVINGSTON VAN DE WATER
• 金额: $ 19.51万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-12-01 至 1993-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3291331
• 关键词: RNA splicing; cell cell interaction; cell migration; extracellular matrix; extracellular matrix proteins; fibrin; fibronectins; glycoprotein structure; human tissue; immunocytochemistry; in situ hybridization; inflammation; laboratory rat; macrophage; monocyte; phagocytes; phagocytosis; protein biosynthesis; protein structure function; tissue /cell culture; wound healing

Extracellular matrix proteins, including fibronectin (FN), provide an important means for modulating of cell function. During inflammation and wound healing, plasma FN (pFN) extravasates and is incorporated into fibrin gels that are thought to serve as a provisional matrix for the migration of a variety of inflammatory cells as well as keratinocytes and fibroblasts. When tested in culture, pFN modulates certain functions of mononuclear phagocytes, including, phagocytosis, migration, synthesis and secretion. This adhesive glycoprotein is synthesized by macrophages and also enhances certain activities of these cells. Fibronectin is not a single protein but comprises a group of closely related glycoproteins which arise by alternative splicing within a single gene transcript. It is now clear that different cells secrete different forms of fibronectin, however the structure of fibronectins produced by macrophages is unknown. This proposal is concerned with elucidating the structure and function of fibronectins produced by macrophages during inflammation. Preliminary evidence, obtained by in situ hybridization with domain-specific fibronectin probes, indicates that these cells modulate the forms of fibronectin produced during wound healing. Experiments are proposed, utilizing this methodology, as well as RNA mapping and immunocytochemistry, to determine if macrophages in delayed hypersensitivity reactions and granulomas also express alternatively spliced forms of fibronectin. These data provide the basis for experiments, using recombinant fibronectins, to determine if spliced domains within this protein alter specific macrophage functions. A third part of this study proposes experiments to establish culture conditions which modulate fibronectin synthesis and alternative splicing patterns. These experiments are expected to provide new insights into the functions of specific domains within fibronectin, the role that alternatively spliced forms of fibronectin and macrophages play during inflammation, and may ultimately provide the basis for therapeutic modulation of macrophage function during wound healing.

细胞外基质蛋白，包括纤连蛋白（FN），提供了一种新的免疫抑制剂。 调节细胞功能的重要手段。 在炎症和 伤口愈合时，血浆FN（pFN）外渗并掺入纤维蛋白中 凝胶被认为是作为临时基质的迁移， 多种炎性细胞以及角质形成细胞和成纤维细胞。 当在培养物中测试时，pFN调节单核细胞的某些功能 吞噬细胞，包括，吞噬作用，迁移，合成和分泌。 这种粘附性糖蛋白由巨噬细胞合成， 这些细胞的某些活动。 纤连蛋白不是单一的蛋白质， 包括一组密切相关的糖蛋白， 在单个基因转录本内的选择性剪接。 现在已经清楚 不同的细胞分泌不同形式的纤连蛋白，然而， 巨噬细胞产生的纤连蛋白的结构是未知的。 本建议涉及阐明的结构和功能 炎症期间巨噬细胞产生的纤维连接蛋白。 初步 证据，通过原位杂交获得与域特异性 纤连蛋白探针，表明这些细胞调节的形式， 在伤口愈合过程中产生的纤连蛋白。 提出了实验， 利用这种方法，以及RNA作图和免疫细胞化学， 以确定巨噬细胞是否在迟发性超敏反应中， 肉芽肿还表达选择性剪接形式的纤连蛋白。 这些 这些数据为使用重组纤连蛋白的实验提供了基础， 确定这种蛋白质内的剪接结构域是否改变了特定的巨噬细胞 功能协调发展的 本研究的第三部分提出了建立实验 调节纤连蛋白合成的培养条件和替代的 拼接模式 这些实验有望为这些功能提供新的见解 选择性剪接的作用， 纤维连接蛋白和巨噬细胞的形式在炎症过程中发挥作用， 最终为巨噬细胞的治疗性调节提供基础 在伤口愈合过程中发挥作用。