NORMAL AND ABERRANT MECHANISMS OF INFLAMMATION, REPAIR AND REGENERATION

这项研究计划的目的是确定分子 调节炎症过程的机制。 的一个关键 炎症过程的介质是TGF-β 1，我们最近的研究 已经集中在TGF-β-1纯合子无效小鼠，其中TGF-β-1基因在小鼠中表达。 β-1已经被灭活作为自身免疫样病理学的模型 类似于干燥综合征 此外，除了免疫调节之外， TGF-β 1被认为对愈合和组织修复至关重要 因为它对间充质细胞的生长和合成有影响。 在 在这方面，我们利用TGF-β 1基因靶向突变体 过表达TGF-β-1（TGF-β-1转基因）或其中 TGF-β-1已失活（TGF-β-1-/-;无效突变）或 部分失活（TGF-β-1 +/-;无效突变杂合子）， 探索这种肽在纤维病理学模型中的作用。 曼氏血吸虫，一种细胞外寄生虫， 在许多发展中国家的肝纤维化， 它的卵进入肝脏后引起的炎症反应。 持续性肉芽肿反应导致基质合成延长 以及肝纤维化，在此期间产生TGF-β-1。 矩阵 对曼氏血吸虫自然感染的反应 蠕虫在TGF-β-1基因靶向小鼠中表现出不同的特征， 与他们的TGF-β-1水平一致。 虽然纤维化 临床表现似乎依赖于TGF-β 1水平，纤维化不是 在没有TGF-β-1的情况下消除，在小鼠中也不是压倒性的 过度表达纤维化肽。 这些意见强调， 复合物中涉及的信号的多因素性质 这和其他纤维化疾病的病理生理学。 然而，作为一个 作为细胞因子级联反应中的一个环节，TGF-β-1是一个潜在的靶点， 纤维化疾病的新疗法。 另一种效应分子 炎症和修复是一氧化氮（NO），其合成是 由TGF-β调节。

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.