REGULATION OF LIVER SPECIFIC GENE EXPRESSION

描述：(改编自调查人员的摘要)。肝为本，肝为本 负责产生血浆和其他必需蛋白质的主要器官 用于化合物的基本新陈代谢和解毒。鉴于 过去十年的研究表明，这些肝脏蛋白质是 很大程度上是由于肝脏特异性基因表达的结果 肝脏富集型转录因子的确切作用机制尚不清楚 实现了肝脏特异性转录。例如，许多问题 肝细胞核因子4(HNF-4)的作用机制尚不清楚， 决定肝脏功能的最重要的转录因子之一 40多个靶基因的表型和调节，包括那些参与 葡萄糖、脂肪酸和胆固醇代谢，血液凝固，以及 化学解毒。因此，这项提议的目标是 通过研究三个方面阐明肝脏特异性基因表达的机制 HNF-4的重要方面：(1)申请人最近表明，由于 其强大且专有的同源二聚活性和专有的核 定位，HNF-4在核受体中定义了一个新的亚群 超级大家庭。他们建议研究特定的氨基酸，这些氨基酸 确定同源二聚化与异源二聚化以及蛋白质的作用 受体功能中的二聚化。这将通过理性的方式实现 基于已知基因的定点突变研究 关于其他受体以及从自然发生的突变 新近在成熟期糖尿病患者中发现的HNF-4 年轻人(MODY1)；(2)申请者将研究 通过分析HNF-4与HNF-4之间的相互作用实现转录激活 HNF-4、共激活子、共抑制子和基本转录机制 通过体内和体外测试；以及(3)申请者将在 体外系统研究HNF-4和HNF-4之间的转录协同作用 另一种肝脏富集型转录因子C/EBPα 载脂蛋白B基因启动子。两种富肝药的协同作用 转录因子可以解释肝脏特异性基因的表达 和其他基因。因为HNF-4已经直接或间接地与 几种人类疾病，包括动脉粥样硬化、肝炎、血友病、 肝癌的发生，以及最近的糖尿病，详细的机制 对HNF-4功能的了解不仅将有助于揭示肝脏特异性基因 同时也为核受体的表达和作用提供了基础 多种治疗试剂未来可能的发展方向 疾病的威胁。

DESCRIPTION: (Adapted from the investigator's abstract). The liver is the primary organ responsible for producing plasma and other proteins essential for basic metabolism and detoxification of chemical compounds. Whereas research during the past decade has shown that these liver proteins are produced largely as a result of liver-specific gene expression mediated by liver-enriched transcription factors, it is not known exactly how liver-specific transcription is achieved. For example, many questions remain about the mechanism of action of hepatocyte nuclear factor 4 (HNF-4), one of the most important transcription factors for determining the hepatic phenotype and regulator of over 40 target genes, including those involved in glucose, fatty acid, and cholesterol metabolism, blood coagulation, and chemical detoxification. The goal of this proposal, therefore, is to elucidate the mechanism of liver-specific gene expression by studying three important aspects of HNF-4: (1) The applicants recently showed that due to its strong and exclusive homodimerization activity and exclusive nuclear localization, HNF-4 defines a new subgroup in the nuclear receptor superfamily. They propose to investigate the specific amino acids that determine homo- vs. heterodimerization as well as the role of protein dimerization in receptor function. This will be achieved by rationally based site-directed mutagenesis studies derived from what is already known about other receptors as well as from a naturally occurring mutation in HNF-4 that was recently found in patients with maturity-onset diabetes of the young (MODY1); (2) The applicants will examine the mechanism of transcriptional activation by HNF-4 by analyzing the interaction between HNF-4, co-activators, co-repressors, and the basal transcription machinery by in vivo and in vitro assays; and (3) The applicants will establish an in vitro system to investigate the transcriptional synergy between HNF-4 and another liver-enriched transcription factor, C/EBP alpha, on the apolipoprotein B gene promoter. Synergy between tow liver-enriched transcription factors could explain liver-specific gene expression for this and other genes. Since HNF-4 has been directly or indirectly linked to several human diseases, including atherosclerosis, hepatitis, hemophilia, hepatocarcinogenesis, and, most recently, diabetes, detailed mechanistic knowledge of HNF-4 function will not only shed light on liver-specific gene expression and the action of nuclear receptors but also provide a basis for the possible future development of therapeutic reagents for a wide variety of diseases.