C/EDB BETA AND CHOP IN EPIDERMAL DIFFERENTIATION

哺乳动物的皮肤是一个重要的器官， 电解质平衡，排除毒素和病原体，并参与 免疫监视 这些职能主要归功于 皮肤的上皮层（表皮）。表皮细胞紊乱 在牛皮癣等疾病或环境损伤中发挥作用 例如暴露于紫外线，是由于 角质形成细胞增殖和分化的精确平衡， 构成正常的表皮分化程序。 这种平衡 在细胞内基因转录水平上由一种 各种转录因子的身份和机制， 行动现在才受到赞赏。 这项提案将考验 一个相对较新的核转录家族 CCAAT-增强子结合蛋白（C/EBP）是一种重要的免疫调节因子， 在表皮分化中起重要调节作用。 基于 初步数据表明，C/EBPS存在于 角质形成细胞的皮肤，在体内和体外，建议 实验将建立，在因果关系的方式，如何两个成员的 C/EBP家族（C/EBP β和CHOP）可能是正确的关键， 表皮分化程序的有序进展。 稳定 角质形成细胞系，表达强力霉素诱导型转基因， 编码C/EBP β和CHOP的激活剂和抑制剂（包括 反义RNA和C/EBP的抑制性蛋白同种型）将被 在体外钙依赖性分化模型中研究。 将测定生长和分化参数的变化 在用强力霉素诱导转基因后。 作为体内 与这些研究相关，将移植稳定的角质形成细胞系， 在裸鼠的背上，测试强力霉素诱导的变化， 在移植部位形成的表皮中。 这些研究的结果可能 加强我们对控制从 增殖到分化，以及在后来的事件如凋亡中， 在表皮中。 这些研究将为以后的研究奠定基础。 观察到的C/EBP β和CHOP变化的意义研究 在银屑病和暴露于紫外线的皮肤中表达。 因此， 在C/EBP β和CHOP调节的基因表达中可能涉及 不仅在正常的平衡增殖和分化， 表皮，但也在表皮疾病和皮肤的反应 环境伤害。

Mammalian skin is a vital organ that serves to maintain fluid and electrolyte balance, exclude toxins and pathogens, and participate in immune surveillance. These functions are largely attributable to the epithelial layer of the skin (the epidermis). Derangements in epidermal function in diseases such as psoriasis, or in environmental injuries such as exposure to ultraviolet light, result from abnormalities in the precise balance of keratinocyte proliferation and differentiation that constitute the normal epidermal differentiation program. This balance is regulated within cells at the level of gene transcription by a variety of transcription factors whose identities and mechanisms of action are only now being appreciated. This proposal will test the hypothesis that a relatively new family of nuclear transcription factors, the CCAAT-enhancer binding proteins (C/EBPs), plays an important regulatory role in epidermal differentiation. Based upon preliminary data that demonstrate the presence of C/EBPS in keratinocytes of the skin, both in vivo and in vitro, the proposed experiments will establish, in a causal manner, how two members of the C/EBP family (C/EBPbeta and CHOP) may be critical for the proper and orderly progression of the epidermal differentiation program. Stable keratinocyte cell lines, expressing doxycyline-inducible transgenes that encode both activators and inhibitors of C/EBPbeta and CHOP (including antisense RNA, and inhibitory protein isoforms of C/EBPs) will be studied in a calcium-dependent differentiation model in vitro. Alterations in parameters of growth and differentiation will be assayed after induction of the transgenes with doxycycline. As an in vivo correlate to these studies, stable keratinocyte lines will be grafted onto the backs of nude mice, to test for doxycycline-inducible changes in the epidermis formed at the graft site. Results of these studies may enhance our understanding of mechanisms that govern the switch from proliferation to differentiation, and in later events such as apoptosis, in the epidermis. These studies will build a foundation for later studies on the significance of observed changes in C/EBPbeta and CHOP expression in psoriasis and in skin exposed to UV light. Thus, changes in C/EBPbeta and CHOP-regulated gene expression are probably involved not only in the normal balance proliferation and differentiation in the epidermis, but also in epidermal disease and in responses of the skin to environmental injury.