(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.
