STUDY OF MICE IN WHICH THE TGF BETA GENE HAS BEEN DISRUPTED

在三种转化生长因子-β亚型中，1型转化生长因子-β在 大多数组织和在损伤、修复和修复中调节最敏锐的组织 疾病发病机制。尽管他们缺乏任何明显的发展 缺陷，转化生长因子-β1基因已被靶向敲除的小鼠 裂解在多灶性炎症的3周龄时死亡 疾病。免疫抑制治疗包括雷帕霉素， 地塞米松、抗CD4、抗CD8可延长转化生长因子-β1的寿命 零老鼠。这使得研究4-5周龄小鼠的伤口愈合成为可能 其中母体转移的转化生长因子-β1已经耗尽。尽管 转化生长因子-β1在伤口愈合中的突出作用，没有延迟闭合 转化生长因子-b1基因缺失小鼠的伤口。然而，形成的速度 肉芽组织数量和胶原沉积减少 与野生型相比，产仔数和疤痕也减少了。数据 表明从血小板释放转化生长因子-β不是必需的 启动组织修复，并提示代偿机制， 可能涉及其他细胞因子或其他转化生长因子-b亚型，可能会克服 转化生长因子-β1缺失对缺陷型小鼠的影响。转化生长因子-β1的其他研究 Null小鼠已经显示出几个受抑制的mRNAs表达 电子传输链的线粒体编码成分， 与高尔基体和线粒体的超微结构异常一致 转化生长因子-β1基因缺失小鼠的肝、心和肺细胞的免疫组化结果提示 能量不足和囊泡运输受损。功能研究已经 结果表明，虽然单个电子链的最大容量 各组分在空白鼠中未发生改变，有显著差异 心脏组织的氧化能力下降。此外，研究 与来自这些小鼠的肝细胞系显示零细胞 氧化率低于野生型细胞的25%。治疗 无论是空白细胞还是野生型细胞，在体外都会导致快速 线粒体基因表达上调。它还没有实现。 确定这种治疗是否会逆转氧化缺陷 新陈代谢。目前的调查旨在确定 转化生长因子-β1调节细胞能量和表达的机制 线粒体基因。

Of the three TGF-b isoforms, type 1 TGF-b is both the most abundant in most tissues and the most acutely regulated in injury, repair, and in disease pathogenesis. Although they lack any obvious developmental defects, mice in which the TGF-b1 gene has been knocked out by targeted disruption die at about 3 weeks of age of multifocal inflammatory disease. Immunosuppressive treatments including rapamycin, dexamethasone, anti-CD4, and anti-CD8 can prolong the life of the TGF-b1 null mice. This has enabled study of wound healing in 4-5 week old mice in which maternally- transferred TGF-b1 has been depleted. Despite the prominent role of TGF-b1 in wound healing, there is no delay in closure of incisional wounds of TGF-b1 null mice. However, the rate of formation and amount of granulation tissue and collagen deposition is reduced compared to wildtype littermates and scarring is also reduced. The data show that release of TGF-b1 from platelets is not essential to initiation of tissue repair and suggest that compensatory mechanisms, possibly involving other cytokines or other TGF-b isoforms, may overcome the effects of loss of TGF-b1 in null mice. Other studies in the TGF-b1 null mice have shown suppressed expression of the mRNAs for several mitochondrially encoded components of the electron-transport chain, consistent with ultrastructural abnormalities in Golgi and mitochondria of cells of liver, heart, and lung of TGF-b1 null mice suggestive of an energy deficit and impaired vesicular transport. Functional studies have shown that whereas maximal capacity of individual electron chain components is not altered in the null mice, there is a significant decrease in the oxidative capacity of heart tissue. Moreover, studies with hepatocyte cell lines derived from these mice show that null cells have less than 25% the oxidative rate of wildtype cells. Treatment of either null or wildtype cells with TGF-b in vitro results in rapid upregulation of expression of mitochondrial genes. It is yet to be determined whether such treatment will reverse the deficit in oxidative metabolism. Present investigations are aimed at determining the mechanism whereby TGF-b1 regulates cellular energetics and expression of mitochondrial genes.