FIBRONECTINS ROLE IN PERICELLULAR MATRIX ORGANIZATION

基于我们以前和正在进行的研究，纤维连接蛋白（FN）- a 多功能二聚体糖蛋白在血浆，基底膜， 结缔组织基质-参与宿主防御，维持 肺结构和胶原沉积。 这些多重的生物学角色 可能是由于FN通过特定位点或结构域结合到其他 结构大分子，自身和受体武装细胞。 而 这一总体方案已经确立，细胞和分子基础 FN与细胞和结缔组织成分的相互作用 目前尚不清楚，但对于阐明FN在肺组织中的作用至关重要。 结构和功能。 我们已经开发和应用了新的方法， 过去三年，包括一个域特异性抗FN抗体库 和具有确定的生物活性的片段，以及生物化学和 形态学技术来批判性地评价FN的基础 与细胞的相互作用和结缔组织基质的组织。 这些方法现在将应用于以下具体目标：1） FN在超分子组织和其他沉积中的作用 细胞周基质成分，包括胶原蛋白和糖胺聚糖 在成纤维细胞培养中。 2)细胞周围基质的作用机制 组织成纤维细胞培养物。 3)FN与细胞的相互作用 在两个对比模型中：人肺泡巨噬细胞， 肺成纤维细胞，使用FN细胞受体和异源 混合实验，以确定细胞外基质的要求 由FN分泌细胞形成。 我们的研究将带来新的 知识和工具的基本理解FN的基础 生物活性，并有助于清楚地描绘FN的作用， 其他器官的结构和功能。 这些信息将提供一个 诊断和最终治疗干预的合理基础 肺和其他疾病的特点是异常组织的 结缔组织基质 朝着这个方向迈出的有希望的第一步是 我们抑制肺成纤维细胞培养物中胶原沉积的能力， 选择性抑制FN基质形成。

Based on our previous and ongoing studies, fibronectin (FN) - a multifunctional dimeric glycoprotein in plasma, basal lamina, and connective tissue matrices - participates in host defense, maintenance of lung architecture, and collagen deposition. These multiple biologic roles are possible by virtue of FN binding via specific sites or domains to other structural macromolecules, to itself, and to receptor armed cells. While this general scheme is well established, the cellular and molecular basis of FN's interactions with cells and with connective tissue components is not presently understood, but is critical for elucidating FN's role in lung structure and function. We have developed and applied new methods over the past three years, including a library of domain specific anti-FN antibodies and fragments with defined biologic activity, as well as biochemical and morphologic techniques to critically evaluate the basis of FN's interactions with cells and organization of connective tissue matrices. These methods will now be applied to the following specific aims: 1) The role of FN in supramolecular organization and deposition of other pericellular matrix components, including collagen and glycosaminoglycans in fibroblast culture. 2) The mechanisms of pericellular matrix organization in fibroblast cultures. 3) The interaction of FN with cells in two contrasting models: the human alveolar macrophage, and cultured lung fibroblasts, using antibodies to the FN cell receptor and heterologous mixing experiments to determine the requirements for extracellular matrix formation by FN secreting cells. Together, our studies will lead to new knowledge and tools fundamental to understanding the basis of FN's biological activities, and help to clearly delineate FN's role in lung and other organ structure and function. This information will provide a rational basis for diagnostic and ultimately theraputic intervention in lung and other diseases characterized by abnormal organization of connective tissue matrices. A promising first step in this direction is our ability to inhibit collagen deposition in lung fibroblast cultures by selective inhibition of FN matrix formation.