REGULATION OF KERATINIZATION BY PEPTIDE GROWTH FACTORS

角质形成细胞，表皮的主要细胞，一方面提供 机械保护，另一方面参与免疫 防御也是。 免疫保护部分由角质形成细胞提供 激活，其出现在病理条件下，例如伤口 愈合、过敏和炎症反应。 针对表皮 损伤时，角质形成细胞变得“活化”，产生并响应生长 因子和细胞因子，成为迁移和生产的组成部分， 基底膜 在活化的角质形成细胞中，角蛋白K#5和K#14是 被过度增殖/活化特异性角蛋白K#6和K#16取代， 其可以被认为是激活特异性标记。 构成这一提议基础的假设指出， 选择哪种角蛋白将由角质形成细胞表达， 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。 该建议的目的是通过以下方式确定分子机制： 其中肽因子调节角质形成细胞活化， 分化，特别是EGF，TGF β和干扰素γ，调节 角蛋白基因的表达。 具体而言，目的是：确定转录的影响， 这三种多肽因子的角蛋白基因，绘制DNA序列， 负责多肽作用的角蛋白基因， 表征作用于这些序列的核蛋白，并将其与 这些核蛋白与角蛋白基因表达的功能， 正常皮肤和病理条件下。 实验遵循一个共同的路径：从识别效果 多肽生长因子对角蛋白基因表达的影响， 表征相应的转录因子，然后 转录因子的纯化和克隆，抗体的产生 最后分析转录因子的相互作用及其作用 在表皮疾病中。 这些实验是非常重要的，因为它们将导致知识 在分子水平上的转录相互作用 在改变角质细胞生理学的多肽生长因子中。

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.