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亚型 在大多数组织中含量丰富，对损伤的调节最严格， 修复，以及各种疾病的发病机制。尽管他们缺乏 任何明显的发育缺陷，在转化生长因子-β1基因具有 被定向干扰击倒，在大约3周大时死亡 多灶性炎症性疾病伴随而来的是显著的 这些小鼠血清中的一氧化氮水平升高。我们有 研究了这些小鼠的自身免疫表型，并证明， 通过将这些小鼠回交到主要组织相容性抗原II上 无背景、自身抗体和组织产生 炎症依赖于MHC-II类抗原的表达 存在CD4+T细胞。这种交叉增强了转化生长因子-β1在血管内皮细胞中的作用 造血导致的骨髓增殖性疾病与突出 髓外髓增生症。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 被用来延长转化生长因子β1缺失小鼠的寿命。这 现在使研究4-5周龄小鼠的伤口愈合成为可能 母体转移的转化生长因子-β1已经耗尽。最后， 差异显示结果显示，ND2、a 线粒体编码的电子传输链的组成部分，是 在转化生长因子-β1缺失的小鼠中被抑制。这导致了示威活动 这种酶的几个线粒体编码成分级联 被协调地抑制，这一发现与观察一致 神经细胞高尔基体和线粒体超微结构异常的研究 转化生长因子-β1基因缺失小鼠的肝、心和肺 提示能量不足和水泡运输受损。我们 已经表明，转化生长因子-β1(-/-)和转化生长因子-β1(+/+)的治疗 体外培养的含有转化生长因子-β的细胞可迅速上调 线粒体基因的表达。目前的调查旨在 在确定转化生长因子-β1调节血管内皮细胞生长因子表达的机制时 线粒体基因及其对细胞能量学的影响。

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, repair, and 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 autoimmune phenotype in these mice and demonstrated, by backcrossing these mice onto an major histocompatibility antigen II null background, that generation of autoantibodies and tissue inflammation is dependent on expression of MHC class II antigen and the presence of CD4+ T-cells. This cross enhances effects of TGF-beta1 on hematopoiesis resulting in myeloproliferative disease with prominent extramedullary myeloplasia. 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. Finally, use of differential display showed that expression of ND2, a mitochondrially encoded component of the electron-transport chain, was suppressed in TGF-beta1 null mice. This has led to the demonstration that several mitochondrially-encoded components of this enzyme cascade are coordinately suppressed, a finding consistent with the observation of ultrastructural abnormalities in Golgi and mitochondria of cells of liver, heart, and lung of TGF-beta1 null mice which are strongly suggestive of an energy deficit and impaired vesicular transport. We have shown that treatment of either TGF-beta1 (-/-) and TGF-beta1 (+/+) cells with TGF-beta in vitro results in rapid upregulation of expression of mitochondrial genes. Present investigations are aimed at determining the mechanism whereby TGF-beta1 regulates expression of mitochondrial genes and its effects on cellular energetics.