HNF-1 AND DEVELOPMENTAL CONTROL OF FIBRINOGEN PRODUCTION

最近在几个国家进行的研究得出了一致的结论， 结论纤维蛋白原水平是一个主要的危险因素， 心血管疾病 与高水平相关的风险等于 或超过血清胆固醇、高血压、吸烟的风险， 糖尿病和肥胖症。 此外，流行病学数据表明， 纤维蛋白原水平升高在以下发病机制中起作用： 心血管疾病和与限制性多态性相关， 纤维蛋白原位点。 纤维蛋白原的产生在很大程度上 由转录因子肝细胞核因子1或 HNF-1，与纤维蛋白原基因的控制区相互作用 以及其他肝脏特异性基因。 我们已经分离了HNF-1的cDNA 发现它含有一个同源结构域， 负责无脊椎动物的模式形成，也是一个遥远的 转录激活因子POU家族成员。 我们的目标是 了解这种蛋白质的功能以及它在发育过程中 监管. 具体而言，我们将开始完成以下测序： cDNA和基因。 这些信息将用于分析 通过丙氨酸取代突变分析HNF-1的功能区 并通过使用HNF-1的部分来补充良好的功能， 特征突变是已知的转录激活因子。 的作用 HNF-1在肝细胞分化和发育中的作用将通过 确定蛋白质在去分化细胞中的表达是否导致 内源性纤维蛋白原基因的表达。 在第二种方法中， 将决定是否感应影响，负责 肝脏和其他器官的形成是通过直接控制 HNF-1在发育中的胚胎中。 最后，我们将利用 观察到视黄酸诱导F9中HNF-1的产生 细胞系来定义发育所需的事件， 调节HNF-1和与HNF-1合作的分子， 激活肝脏特异性基因 在这五年结束时，我们 我希望能描述出调节细胞和分子活动的特征， HNF-1在发展过程中的作用，并有准确的理解， 器官形成和纤维蛋白原和其他肝脏的激活- 特定基因

Recent studies conducted in several countries have come to the unanimous conclusion that fibrinogen levels are a major risk factor for cardiovascular disease. The risk associated with elevated levels equals or exceeds the risk for serum cholesterol, high blood pressure, smoking, diabetes and obesity. Furthermore, the epidemiologic data suggest that elevated fibrinogen levels play a role in the pathogenesis of cardiovascular disease and correlate with a restriction polymorphism in the fibrinogen locus. Production of fibrinogen is in large part controlled by the transcription factor, hepatocyte nuclear factor 1 or HNF-1, which interacts with the control regions for the fibrinogen genes as well as other liver-specific genes. We have isolated a cDNA for HNF-1 and found that it contains a homeodomain similar to that found in genes responsible for pattern formation in invertebrates, and also is a distant member of the POU family of transcriptional activators. Our goal is to understand how this protein functions and how it is developmentally regulated. Specifically, we will begin by completing the sequencing of the cDNA and gene. This information will be used to dissect the functional regions of HNF-1 by analysis of alanine-substitution mutations and by using portions of HNF-1 to complement the function of well- characterized mutations is known transcriptional activators. The role of HNF-1 in hepatocyte differentiation and development will be explored by determining if expression of the protein in dedifferentiated cells leads to expression of endogenous fibrinogen genes. In a second approach we will determine if the inductive influences that are responsible for the formation of the liver and other organs operate by directly controlling HNF-1 n the developing embryo. Finally, we will make use of the observation that retinoic acid induces the production of HNF-1 in the F9 cell line to define the events that are required for the developmental regulation of HNF-1 and the molecules which cooperate with HNF-1 to activate liver-specific genes. At the end of this five year period, we hope to have characterize the cellular and molecular events that regulate HNF-1 during developing and to have a precise understanding of its role in organogenesis and the activation of the fibrinogen and other liver- specific genes.