NF-KAPPA BS IN VIVO ROLE IN DERMATITIS AND ANGIOGENESIS

描述(来自应用程序)： 多效性转录因子NF-kappaB是 免疫反应和炎症。有几个基因参与了 血管生成与白细胞血管生成(血管内皮生长因子、血管内皮生长因子受体、血管细胞黏附分子、 ICAM、ELAM)被认为受核因子-kappaB调控或含有核因子-kappaB 它们的启动子中的结合位点。然而，这些数据中的绝大多数 已经在体外系统中积累起来。众所周知，在 体外系统可能不能准确地描述体内事件。为了 为了研究核因子-kappaB在体内的作用，这项资助提出了以下建议： 1)IkappaBalpha缺陷型皮炎发生的研究 老鼠。在这个动物模型中，IkappaBalpha基因通过 同源重组。这些动物发展成一种严重的大范围传播 出生后第一周就会出现皮炎。这种皮炎的发展是 在出生后3至6天内发生在时间上可预见的，这将 允许对皮炎的发展进行分期研究。具体来说， 血管内皮生长因子及其靶点的表达将 根据表达的时间和空间模式进行研究。 其他可能与皮炎有关的基因，如基质蛋白水解酶 被调查。 2)开发四环素诱导/阻遏系统，创造动物 利用核因子-kappaB相关基因的真皮炎症模型 系统。预计这些型号还将允许 调查员直接控制皮炎和其他疾病的发病 炎症性疾病使空间和时间基因的研究成为可能 如上所述的表达。此外，这些动物可以作为资源 用于药物开发和筛选，因为它们将代表更明确的 实验系统。一旦四环素可诱导/阻遏系统 都是为皮肤研究而开发的，它们可以进一步开发来 开发其他疾病的动物模型。

DESCRIPTION (from the application): The pleiotropic transcription factor NF-kappaB is a major component of the immune response and inflammation. Several of the genes involved in angiogenesis and leukocyte evascularization (vegf, vegf receptor, VCAM, ICAM, ELAM) are thought to be regulated by NF-kappaB or contain NF-kappaB binding sites in their promoters. However, the vast majority of these data have been accumulated using in vitro systems. It is well known, that in vitro systems may not accurately portray in vivo events. In order to investigate NF-kappaB's role in vivo, this grant proposes the following: 1) Study of the development of dermatitis in the IkappaBalpha deficient mice. In this animal model, the IkappaBalpha gene has been deleted via homologous recombination. These animals develop a severe wide-spread dermatitis in the first week of life. The development of this dermatitis is temporally predictable occurring between 3 to 6 days after birth, which will allow for a staged study of the development of dermatitis. Specifically, the expression of vascular endothelial growth factors and their targets will be investigated in terms of the temporal and spatial pattern of expression. Other genes potentially involved in dermatitis such as matrix proteases will be investigated. 2) Develop the tetracycline inducible/repressible systems to create animal models of dermal inflammation exploiting the genes involved in the NF-kappaB system. It is anticipated that these models will also allow the investigator to directly control the onset of dermatitis and other inflammatory diseases allowing the study of spatial and temporal gene expression as discussed above. Further, these animals may serve as resource for drug development and screening as they will represent a more defined experimental system. Once the tetracycline inducible/repressible systems have been developed for cutaneous study, they can be further exploited to develop animal models for other diseases.