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

对 TGF Beta 基因被破坏的小鼠的研究

• 批准号: 2463689
• 负责人: A B ROBERTS
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2463689
• 关键词: Golgi apparatus; MHC class II antigen; animal genetic material tag; autoimmune disorder; blocking antibody; dexamethasone; gene induction /repression; helper T lymphocyte; hematopoiesis; laboratory mouse; metabolism disorder; mitochondria; nitric oxide; protein isoforms; sirolimus; transforming growth factors

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.

在三种TGF-β亚型中，1型TGF-β都是最常见的。 在大多数组织中含量丰富，并且在损伤中受到最剧烈的调节， 修复，以及各种疾病的发病机制。 虽然他们缺乏 任何明显的发育缺陷，其中TGF-β 1基因具有 被有针对性的破坏击倒，在大约3周龄时死亡。 多灶性炎性疾病 这是伴随着显着 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， 通过将这些小鼠与主要组织相容性抗原II 零背景，自身抗体和组织的产生 炎症依赖于MHC II类抗原的表达， 存在CD 4 + T细胞。 这种交叉增强了TGF-β 1对 骨髓增生性疾病的造血功能， 髓外骨髓增生 在另一种方法中，免疫抑制 治疗包括雷帕霉素、地塞米松、抗CD 4和抗CD 8 用于延长TGF-β 1缺失小鼠的寿命。 这 现在已经使研究4-5周大的老鼠伤口愈合成为可能 其中母体转移的TGF-β 1已经耗尽。 最后， 差异显示ND 2， 电子传递链的一个重要编码成分， 在TGF-β 1缺失小鼠中抑制。 这导致了示威游行 这种酶级联反应的几种基因编码成分 都被协调地抑制了，这一发现与观察结果一致， 细胞的高尔基体和线粒体的超微结构异常 TGF-β 1基因敲除小鼠的肝脏、心脏和肺， 提示能量缺乏和囊泡运输受损。 我们 已经表明，TGF-β 1（-/-）和TGF-β 1（+/+） 体外培养的TGF-β细胞导致 线粒体基因的表达。 目前的调查旨在 在确定TGF-β 1调节 线粒体基因及其对细胞能量学的影响。