Regulation of Liver-Specific Gene Expression

肝脏特异性基因表达的调节

• 批准号: 7837560
• 负责人: FRANCES M. SLADEK
• 金额: $ 3.39万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7837560
• 关键词: Address; Adult; Affect; Alternative Splicing; Atherosclerosis; Cell Cycle; Cell Cycle Inhibition; Cell Proliferation; Colon Carcinoma; Cytoplasm; DNA Binding; DNA Binding Domain; Data; Development; Diabetes Mellitus; Diet; Disease; Drug Delivery Systems; Essential Genes; Exons; Fetal Liver; Funding; Gene Expression; Gene Expression Regulation; Gene Structure; Gene Targeting; Genes; Genetic Transcription; Genome; Goals; Hemophilia A; Hepatocyte; Human; Intestines; Investigation; Kidney; Knowledge; Letters; Ligands; Link; Liver; Liver Regeneration; Malignant Neoplasms; Maps; Metabolism; Molecular; Mus; Nuclear Receptors; Obesity; Outcome; Pancreas; Phosphorylation; Physiological; Play; Protein Isoforms; Proteins; Public Health; Regulation; Research; Role; Serine; Signal Pathway; Signal Transduction; Stomach; Stress; Techniques; Tissues; Transcript; Tyrosine Phosphorylation; c-myc Genes; design; extracellular; follow-up; hepatocyte nuclear factor; human HNF4A protein; human disease; in vivo; interest; member; metabolomics; mouse model; mutant; promoter; protein degradation; research study; response; transcription factor

DESCRIPTION (provided by applicant): Hepatocyte nuclear factor 4 (HNF4) is a highly conserved member of the nuclear receptor (NR) superfamily of ligand-dependent transcription factors. It is an essential gene, playing a critical role in early development, as well as in the adult in the liver, kidney, pancreas and intestine. HNF4 has been directly linked to several human diseases including diabetes and hemophilia and indirectly linked to others including atherosclerosis and cancer. HNF4 is one of the most abundant transcription factors in the liver. Whereas many target genes have been identified for HNF4, recent genome-scale analyses indicate that there are many more yet to be identified. Recent results indicate, for example, that there may be differences in the target genes of the different isoforms of HNF4 generated by alternative splicing and promoter usage. Furthermore, HNF4 is known to be a heavily phosphorylated protein and to respond to a variety of intra- and extracellular signals; however, only a few of the phosphosites have been mapped and fully characterized. Finally, in addition to its role in intermediary metabolism, there is a growing body of evidence indicating that HNF4 may also play a role in regulating the cell cycle. In order to address these issues, we propose the following three Specific Aims: 1) Identify new target genes for HNF4 using genome-scale analysis and an in vivo mouse model to examine the functional differences in HNF4 isoforms; 2) Investigate the role of tyrosine phosphorylation in HNF4 function; and 3) Investigate the role of HNF4 in regulating the cell cycle. The proposed experiments will continue the investigation of the role of HNF4 in liver-specific gene expression using a broad array of modern techniques. The results will further our understanding of the mechanisms of tissue-specific gene regulation. They will also provide invaluable information regarding a variety of human diseases that are linked to HNF4. Finally, as a potential drug target, a more comprehensive knowledge of the genes targeted by HNF4, as well as the signaling pathways that target HNF4, will be essential to developing appropriate therapies. Project Narrative: Our research is relevant to public health because it attempts to decipher the mechanisms by which genes are turned on in the liver and gut. This is critical not only for understanding the causes of diseases such as diabetes, obesity, atherosclerosis and cancer, but also for designing new therapies to treat those diseases.

描述（由申请人提供）：肝细胞核因子4（HNF4）是配体依赖性转录因子核受体（NR）超家族的高度保守成员。它是一种必需基因，在早期发育以及成人的肝脏、肾脏、胰腺和肠道中发挥着关键作用。 HNF4 与糖尿病和血友病等多种人类疾病直接相关，并与动脉粥样硬化和癌症等其他疾病间接相关。 HNF4 是肝脏中最丰富的转录因子之一。尽管 HNF4 的许多靶基因已被鉴定，但最近的基因组规模分析表明还有更多的靶基因有待鉴定。例如，最近的结果表明，通过选择性剪接和启动子使用产生的不同 HNF4 亚型的靶基因可能存在差异。此外，HNF4 是一种高度磷酸化的蛋白质，可对多种细胞内和细胞外信号做出反应。然而，只有少数磷酸位点被绘制出来并得到充分表征。最后，除了在中间代谢中的作用外，越来越多的证据表明 HNF4 还可能在调节细胞周期中发挥作用。为了解决这些问题，我们提出以下三个具体目标：1）利用基因组规模分析和体内小鼠模型来鉴定HNF4的新靶基因，以检查HNF4亚型的功能差异； 2）研究酪氨酸磷酸化在HNF4功能中的作用； 3) 研究HNF4在调节细胞周期中的作用。拟议的实验将利用广泛的现代技术继续研究 HNF4 在肝脏特异性基因表达中的作用。这些结果将进一步加深我们对组织特异性基因调控机制的理解。他们还将提供有关与 HNF4 相关的各种人类疾病的宝贵信息。最后，作为潜在的药物靶点，更全面地了解 HNF4 靶向的基因以及针对 HNF4 的信号通路对于开发适当的疗法至关重要。 项目叙述：我们的研究与公共卫生相关，因为它试图破译肝脏和肠道中基因的开启机制。这不仅对于了解糖尿病、肥胖、动脉粥样硬化和癌症等疾病的原因至关重要，而且对于设计治疗这些疾病的新疗法也至关重要。