STUDY OF MICE IN WHICH THE TGF BETA 1 GENE HAS BEEN DISRUPTED

转化生长因子-β(转化生长因子-β)此前曾被认为与 在胚胎发育和调节细胞增殖和 目的基因的表达。在三种转化生长因子-β亚型中，1型 转化生长因子-β在大多数组织中含量最高，也是最剧烈的 在损伤和修复以及在各种疾病的发病机制中发挥调节作用 疾病。尽管它们没有任何明显的发育缺陷，但在 哪些转化生长因子-β1基因已被靶向干扰消除 在大约3周龄时出现多灶性炎症性疾病。这是 伴随着血清中一氧化氮水平的显著升高 这些老鼠。我们已经调查了可能的引爆事件 这种炎症综合征发现，在检测到任何 组织浸润性，I类和II类主要表达 组织相容性(MHC)抗原在这些小鼠中很高，而通常 在正常产仔的可比组织中检测不到，这表明 转化生长因子-β可能是MHC抗原表达的天然抑制因子。我们有 现在将转化生长因子β1缺失的小鼠与缺乏MHC II类的小鼠进行杂交 基因和缺乏T和B淋巴细胞的裸鼠。双MHC II类/转化生长因子-β1基因敲除显示没有组织渗透，但死于 骨髓增殖性疾病，髓外造血突出， 强调转化生长因子-β1作为血管紧张素转换酶的关键调节因子 造血术。在另一种方法中，免疫抑制治疗 包括雷帕霉素、地塞米松、抗CD4和抗CD8 延长转化生长因子β1基因缺失小鼠的寿命。这现在已经使 4-5周龄小鼠伤口愈合的可能研究 母体转移的转化生长因子-β1已经耗尽。这些方法是 现在为转化生长因子-β和转化生长因子-β之间可能的联系提供了新的见解 能量代谢。数据表明，一种基因的高度表达 与关键的线粒体酶NADH脱氢酶同源的是 由转化生长因子-β1控制，在组织和来源的细胞系中 转化生长因子-β1基因敲除小鼠。转化生长因子-β1(-/-)肝细胞的实验研究 细胞株研究表明，转化生长因子-β1在细胞周期调控中起关键作用。 能量依赖性细胞事件及其关键线粒体的表达 酵素。

Transforming growth factor-beta (TGF-beta) has previously been implicated in embryonic development and in regulating both cell proliferation and expression of target genes. Of the three TGF-beta isoforms, type 1 TGF-beta is both the most abundant in most tissues and the most acutely regulated in injury and repair and in the pathogenesis of various diseases. Although they lack any obvious developmental defects, mice in which the TGF-beta1 gene has been knocked out by targeted disruption die at about 3 weeks of age of multifocal inflammatory disease. This is accompanied by significantly elevated levels of nitric oxide in the serum of these mice. We have investigated the possible initiating event in this inflammatory syndrome and found that, prior to detection of any tissue infiltrates, expression of both class I and II major histocompatibility (MHC) antigens is high in these mice while generally undetectable in comparable tissues in normal littermates, suggesting that TGF-beta may be a natural repressor of MHC antigen expression. We have now crossed the TGF-beta1 null mice with mice lacking the MHC class II gene and with nude mice, which lack T and B lymphocytes. The double MHC class II/TGF-beta1 knockouts show no tissue infiltrates, but die of myeloproliferative disease with prominent extramedullary hematopoiesis, underscoring the role of TGF-beta1 as a critical regulator of hematopoiesis. In another approach, immunosuppressive treatments including rapamycin, dexamethasone, anti-CD4, and anti-CD8 are being used to prolong the life of the TGF-beta1 null mice. This has now made possible the study of wound healing in 4-5 week old mice in which maternally-transferred TGF-beta1 has been depleted. These approaches are now providing new insights into possible links between TGF-beta and energy metabolism. Data suggest that expression of a gene highly homologous to a key mitochondrial enzyme, NADH dehydrogenase, is controlled by TGF-beta1, both in tissues and in cell lines derived from the TGF-beta1 knockout mice. Experiments with TGF-beta1 (-/-) hepatocyte cell lines demonstrate that TGF-beta1 plays a key role in regulation of energy-dependent cellular events and expression of this key mitochondrial enzyme.