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PATHOBIOLOGY OF MACROPHAGE-FIBRONECTIN INTERACTIONS

巨噬细胞-纤连蛋白相互作用的病理学

基本信息

批准号：
2178542
负责人：
LIVINGSTON VAN DE WATER
金额：
$ 22.38万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-12-01 至 1994-11-30
项目状态：
已结题

项目摘要

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，包括纤维连接蛋白(FN)，提供了一种调节细胞功能的重要手段。在发炎期间和伤口愈合，血浆FN(PFN)渗出并并入纤维蛋白被认为是迁移的临时基质的凝胶多种炎症细胞以及角质形成细胞和成纤维细胞。当在培养中测试时，PFN调节单个核细胞的某些功能吞噬细胞，包括吞噬、迁移、合成和分泌。这种粘附性糖蛋白是由巨噬细胞合成的，它还可以增强这些细胞的某些活动。纤维连接蛋白不是单一的蛋白质，但由一组密切相关的糖蛋白组成，它们由单基因转录本中的选择性剪接。现在很明显，不同的细胞分泌不同形式的纤维连接蛋白，然而巨噬细胞产生的纤维连接蛋白的结构尚不清楚。这项提议涉及到阐明细胞的结构和功能炎症过程中巨噬细胞产生的纤维连接蛋白。初步通过与特定区域的原位杂交获得的证据纤维连接蛋白探针，表明这些细胞调节伤口愈合过程中产生的纤维粘连蛋白。提出了实验方案，利用这种方法，以及RNA图谱和免疫细胞化学，为了确定巨噬细胞在迟发型超敏反应和肉芽肿也表达纤维连接蛋白的选择性剪接形式。这些数据为使用重组纤维连接蛋白进行实验提供了基础确定该蛋白内的剪接结构域是否改变了特定的巨噬细胞功能。这项研究的第三部分建议进行实验，以建立调节纤维连接蛋白合成的培养条件及其替代拼接图案。这些实验有望为了解这些功能提供新的见解。纤维连接蛋白中的特定结构域，其作用是选择性地剪接纤维连接蛋白和巨噬细胞在炎症过程中发挥作用，并可能最终为巨噬细胞的治疗调控提供依据在伤口愈合过程中发挥作用。