COLLAGEN BIOSYNTHESIS IN HUMAN SKIN FIBROBLASTS

胶原蛋白是结缔组织的主要成分。它的合成是 在许多疾病过程中改变，在纤维化条件下增加和 伤口愈合不良时出现异常的疤痕和减少。建议数 研究的目的是了解相关的分子机制。 用于：(1)苯甲酰肼抑制胶原合成；以及(2) 米诺地尔对赖氨酰羟化酶表达的抑制作用。在这些人中 将要研究的参数是特定类型的胶原合成， 前胶原mRNA稳定性、前胶原基因转录和 翻译后修饰酶脯氨酸羟基酶和赖氨酸 羟基酶。将通过嵌合体来探索转录机制 含有胶原或赖氨酸羟基酶启动子序列的基因 与适当的报告基因相关联的基因。这些基因将被插入 转化成纤维细胞以检测对启动子活性的影响。最终的 这项研究的目标是识别调节分子并确定 它们与基因相互作用的本质使我们能够设计 可以调节基因表达的附加效应分子。一个 了解米诺地尔或苯甲酸的转录效应 肼可能会导致有效的策略来控制过量 纤维化条件下的胶原堆积。

Collagen is a major component of connective tissue. Its synthesis is altered in many disease processes, increasing in fibrotic conditions and abnormal scarring and decreasing in impaired wound healing. The proposed studies are aimed at understanding the molecular mechanisms responsible for: (1) Inhibition of collagen synthesis by benzoic hydrazide; and (2) inhibition of lysyl hydroxylase expression by minoxidil. Among the parameters that will be studied are type-specific collagen synthesis, procollagen mRNA stability, procollagen gene transcription and posttranslational modifying enzymes prolyl hydroxylase and lysyl hydroxylase. Transcriptional mechanisms will be explored with chimeric genes containing promoter sequences for collagen or lysyl hydroxylase genes linked to appropriate reporter genes. These genes will be inserted into fibroblasts to examine influences on promoter activity. The eventual goal of this research is to identify regulatory molecules and to define the nature of their interaction with genes enabling us to design additional effector molecules that can modulate gene expression. An understanding of the transcriptional effects of minoxidil or benzoic hydrazide may lead to effective strategies for controlling excessive collagen accumulation in fibrotic conditions.