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高血压的主要危险因素。 心血管疾病。与升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糖尿病的发病机制中起一定作用 心血管疾病，并与基因的限制酶基因多态相关。 纤维蛋白原基因座。纤维蛋白原生产在很大程度上 受转录因子控制，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。我们已经分离到一段hnf-1的cdna。 并发现它含有一个与基因中发现的同源结构域类似的结构域 负责无脊椎动物的图案形成，也是一个遥远的 POU转录激活子家族的成员。我们的目标是 了解这种蛋白质如何发挥作用以及它是如何发育的 受监管的。具体地说，我们将从完成 基因和基因的表达。这些信息将被用于剖析 丙氨酸取代突变分析人神经营养因子-1的功能区 通过使用部分HNF-1来补充Well-1的功能- 表征突变的是已知的转录激活剂。的作用 HNF-1在肝细胞分化和发育中的作用 确定该蛋白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，我们 将决定是不是导致 肝脏和其他器官的形成是通过直接控制 HNF-1在发育中的胚胎中表达。最后，我们将利用 维甲酸诱导F9细胞产生HNF-1的观察 细胞系来定义发育所需的事件 人神经营养因子-1及与其协同作用的分子调控 激活肝脏特异性基因。在这五年结束时，我们 希望能够描述调节细胞和分子事件的特征 HNF-1在发育过程中的作用，并对其在 器官发生和纤维蛋白原和其他肝脏的激活- 特定的基因。

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.