REVERSE GENETIC ANALYSIS IN TISSUE INJURY

组织对损伤的反应是多形核细胞的早期返流 以及随后单核/巨噬细胞进入伤口区域。 巨噬细胞来源的有丝分裂因子不仅被认为是 对于正常的伤口愈合是必不可少的，但也与 慢性炎症时可能发生的纤维化。转型增长 因子-β(TGFbeta)，一种促有丝分裂因子，在 组织调节，已被证明是由血小板分泌并激活的 巨噬细胞。 尽管TGFbeta被认为主要发挥着强大的监管作用 通过对其他生长因子和细胞外基质的影响 (导致其整体增加)，TGFβ在体内的作用较差 明白了。本项目的目标是研究转化生长因子β在体内的作用。 通过制备突变型转化生长因子β不仅是不活跃的，而且还将 当野生型转化生长因子β与突变体形成异二聚体时，使其失活。 这利用了以下事实，即TGFbeta被翻译为 前体并被加工成活性蛋白质。 显性的转化生长因子β突变基因将与一个启动子相连，该启动子只有 活跃于激活的巨噬细胞(Visna病毒长末端重复序列)，以及 这种结构将被用来开发转基因模型。它是 首席调查员的最终目标是审查 巨噬细胞衍生的转化生长因子β在慢性炎症中的作用，主要是在肺部。 利用这种转基因模型，可以使用各种实验方法来 产生肺损伤，提供的信息不仅是关于 巨噬细胞源性转化生长因子β在慢性炎症中的作用 正常的伤口愈合。

Tissue responds to damage with an early reflux of polymorphonuclear cells and subsequent influx of monocytes/macrophages into the wound area. Mitogenic factors derived from macrophages have not only been recognized as essential to normal wound-healing, but have also been implicated in the fibrosis that can occur with chronic inflammation. Transforming growth factor-beta (TGFbeta), a mitogenic factor that plays a strong role in tissue regulation, has been shown to be secreted by platelets and activated macrophages. Although TGFbeta is thought to play its strong regulatory role primarily through effects on other growth factors and the extracellular matrix (resulting in its overall increase), the in vivo role of TGFbeta is poorly understood. The goal of this project is to study the effects of TGFbeta in vivo by preparing a mutant TGFbeta that is not only inactive, but also will inactivate wild-type TGFbeta when it forms a heterodimer with the mutant. This takes advantage of the fact that TGFbeta is translated as a prepro-form and is processed to an active protein. The dominant TGFbeta mutant gene will be linked to a promoter that is only active in activated macrophages (visna virus long terminal repeat), and this construct will be used to develop a transgenic model. It is the eventual goal of the principal investigator to examine the role of macrophage-derived TGFbeta in chronic inflammation, primarily in the lung. With this transgenic model, various experimental methods could be used to produce lung damage, providing information not only on the role of macrophage-derived TGFbeta in chronic inflammation but also on its role in normal wound-healing.