REGULATION OF KERATINIZATION BY PEPTIDE GROWTH FACTORS

角质形成细胞是表皮的主要细胞，一方面提供 一方面参与机械保护，另一方面参与免疫 防守也是如此。 免疫保护部分是由角质形成细胞提供的。 激活，出现在病理条件下，如伤口 治愈、过敏和炎症反应。对表皮的反应 损伤后，角质形成细胞被激活，产生并对生长做出反应 因子和细胞因子，变得可迁移，并产生 基底膜。在激活的角质形成细胞中，角蛋白K#5和K#14 被高增殖/激活特异性角蛋白K#6和K#16取代， 它们可以被认为是激活特异的标志物。 构成这一提议基础的假设表明， 角质形成细胞将表达哪些角蛋白蛋白的选择 部分由多肽生长因子和细胞因子决定 确定细胞表型。这一假设得到了 初步结果。 这项提议的目的是通过以下方式确定分子机制 调节角质形成细胞活化的多肽因子和 分化，特别是表皮生长因子、转化生长因子β和干扰素伽马，调节 角蛋白基因的表达。 具体地说，目的是：确定对转录的影响 这三种多肽因子的角蛋白基因，将DNA序列映射到 角蛋白基因负责多肽的作用， 描述作用于这些序列的核蛋白，并相互关联 角蛋白基因表达的核蛋白在细胞中的作用 皮肤正常，处于病理状态。 这些实验遵循一条共同的道路：从识别影响 多肽生长因子对角蛋白基因表达的影响 相应转录因子的特性，随后是 转录因子的纯化和克隆及抗体的产生 最后分析了转录因子的相互作用及其作用 在表皮疾病中。 这些实验非常重要，因为它们将带来知识 在核的分子水平上的转录相互作用 在改变角质形成细胞生理的多肽生长因子中。

Keratinocytes, the predominant cells of the epidermis, provide on one hand mechanical protection and on the other participate in immunological defense as well. The immunological protection is provided in part by keratinocyte activation, which appears in pathological conditions, such as wound healing, allergic and inflammatory reactions. In response to epidermal injury, keratinocytes become "activated", produce and respond to growth factors and cytokines, become migratory and produce components of the basement membrane. In activated keratinocytes keratins K#5 and K#14 are replaced by hyperproliferation/activation-specific keratins K#6 and K#16, which can be considered activation-specific markers. The hypothesis that forms the basis for this proposal states that the choice of which keratin proteins will be expressed by a keratinocyte is determined, in part, by the polypeptide growth factors and cytokines that determine the cell phenotype. This hypothesis is confirmed by the preliminary results. The aims of this proposal are to determine the molecular mechanisms by which the peptide factors that modulate keratinocyte activation and differentiation, in particular EGF, TGFbeta and interferon gamma, regulate expression of keratin genes. Specifically, the aims are to: determine the effects on transcription of keratin genes of these three polypeptide factors, map the DNA sequences in the keratin genes responsible for the effects of polypeptides, characterize the nuclear proteins acting on those sequences, and correlate the function of those nuclear proteins with keratin gene expression in normal skin and in pathological conditions. The experiments follow a common path: from identification of the effects of a polypeptide growth factor on keratin gene expression, to characterization of the corresponding transcription factor, followed by purification and cloning of the transcription factor, antibody production and finally analysis of transcription factor interactions and their role in epidermal diseases. These experiments are very important because they will lead to knowledge of transcriptional interactions at the molecular level in the nucleus among the polypeptide growth factors that change keratinocyte physiology.