NORMAL AND ABERRANT MECHANISMS OF INFLAMMATION, REPAIR AND REGENERATION

这项研究计划的目标是定义分子 调节炎症过程的机制。其中一个关键是 炎症过程的介质是转化生长因子-β1和我们最近的研究 已经专注于转化生长因子-β-1纯合子缺失的小鼠，其中转化生长因子-β-1的基因 β-1作为一种自身免疫样病理模型已经失活 类似于干燥综合征。此外，除了其免疫调节外， 作用，转化生长因子-β-1被认为是愈合和组织修复所必需的 因为它的生长和对间充质细胞的合成影响。在……里面 对此，我们利用了转化生长因子-β-1基因的靶向突变体 过度表达转化生长因子-β1(转化生长因子-β-1转基因)的小鼠或 转化生长因子-β-1失活(转化生长因子-β-1-/-；零突变)或 部分失活(转化生长因子-β-1+/-；零突变杂合子)，至 探索这种多肽在纤维病理模型中的作用。 曼氏血吸虫病，一种胞外寄生虫，是主要原因 在许多发展中国家，肝纤维化的发生会引发肉芽肿 对寄生在肝脏中的卵子作出的炎症反应。 持续的肉芽肿性反应导致基质合成时间延长 和肝纤维化，在此期间产生转化生长因子-β-1。矩阵 曼氏血吸虫自然感染后的产生和纤维化反应 在以转化生长因子-β1基因为靶标的小鼠中，蠕虫表现出不同的特征， 与他们的转化生长因子-β-1水平一致。虽然是纤维化的 临床表现似乎依赖于转化生长因子-β1水平，而纤维化则不是 在缺乏转化生长因子-β-1的情况下消除，在小鼠中也不是压倒性的 过度表达这种致纤维化的多肽。这些观察结果强调了 复合体中涉及的信号的多因素性质 这种和其他纤维性疾病的病理生理学。尽管如此，作为一名 在细胞因子级联中，转化生长因子-β-1代表着一个潜在的靶点 纤维性疾病的新疗法。另一种效应器分子 炎症和修复是一氧化氮(NO)，其合成是 受转化生长因子-β调控。

The objective of this research program is to define the molecular mechanisms that regulate the inflammatory process. One of the key mediators of the inflammatory process is TGF-beta1 and our recent studies have focused on TGF-beta-1 homozygous null mice in which the gene for TGF- beta-1 has been inactivated as a model of autoimmune-like pathology similar to Sjogren's Syndrome. Moreover, beyond its immunoregulatory role, TGF-beta-1 is considered essential to healing and tissue repair because of its growth and synthetic influences on mesenchymal cells. In this regard, we have taken advantage of TGF-beta-1-gene targeted mutant mice which over-express TGF-beta-1 (TGF-beta-1 transgenics) or in which TGF-beta-1 has been inactivated (TGF-beta-1-/-; null mutation) or partially inactivated (TGF-beta-1+/-; null mutation heterozygotes), to explore the role of this peptide in a model of fibropathology. Schistosomiasis mansoni, an extracellular parasite, which is a major cause of hepatic fibrosis in many developing countries, triggers a granulomatous inflammatory reaction in response to its eggs that lodge in the liver. The persistent granulomatous response leads to prolonged matrix synthesis and hepatic fibrosis during which TGF-beta-1 is produced. Matrix production and fibrosis in response to natural infection with S.mansoni worms exhibited distinct profiles in TGF-beta-1 gene targeted mice, consonant with their levels of TGF-beta-1. Although fibrotic manifestations appear dependent on TGF-beta-1 levels, fibrosis is not eliminated in the absence of TGF-beta-1, nor overwhelming in mice overexpressing this fibrogenic peptide. These observations emphasize the multifactorial nature of the signals involved in the complex pathophysiology of this and other fibrotic diseases. Nonetheless, as a link in the cytokine cascade, TGF-beta-1 represents a potential target for novel therapies in fibrotic disorders. Another effector molecule in inflammation and repair is nitric oxide (NO), the synthesis of which is regulated by TGF-beta.