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

在三种TGF-β同种型中，1型TGF-β是最丰富的， 大多数组织和最急性调节损伤，修复， 发病机理虽然他们缺乏明显的发育 缺陷，其中TGF-b1基因已被敲除的小鼠， 破裂在约3周龄多灶性炎性 疾病免疫抑制治疗包括雷帕霉素， 地塞米松、抗CD 4、抗CD 8可延长TGF-β 1的寿命 无效小鼠。这使得能够在4-5周龄小鼠中研究伤口愈合 其中母体转移的TGF-β 1已经耗尽。尽管 TGF-β 1在伤口愈合中的作用突出，没有延迟闭合 TGF-β 1基因敲除小鼠的切口伤口。然而， 肉芽组织和胶原沉积量减少 与野生型同窝仔相比，瘢痕形成也减少。数据 显示从血小板释放TGF-b1对于 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TGF-β亚型，可以克服 TGF-b1缺失对裸鼠的影响。其他关于TGF-β 1的研究 裸小鼠已经显示了几种基因的mRNA表达受到抑制， 电子传输链的编码组件， 与高尔基体和线粒体的超微结构异常一致 TGF-b1基因敲除小鼠的肝、心和肺细胞中， 能量缺乏和囊泡运输受损。功能性研究 表明，尽管单个电子链的最大容量 在无效小鼠中，组分没有改变，存在显著的 降低心脏组织的氧化能力。此外，研究 来自这些小鼠的肝细胞系显示， 其氧化率低于野生型细胞的25%。治疗 在体外用TGF-b的无效或野生型细胞导致快速的 线粒体基因表达的上调。还有待 确定这种治疗是否会逆转氧化应激的不足， 新陈代谢.目前的调查旨在确定 TGF-β 1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.