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（HNF 4）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，在早期发育以及成年后的肝脏、肾脏、胰腺和肠道中起着关键作用。HNF 4与包括糖尿病和血友病在内的几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。HNF 4是肝脏中最丰富的转录因子之一。尽管已经确定了HNF 4的许多靶基因，但最近的基因组规模分析表明还有更多的靶基因有待确定。最近的结果表明，例如，可能有不同的HNF 4异构体产生的选择性剪接和启动子使用的靶基因的差异。此外，已知HNF 4是一种高度磷酸化的蛋白质，并对多种细胞内和细胞外信号作出反应;然而，只有少数磷酸化位点被绘制并充分表征。最后，除了在中间代谢中的作用外，越来越多的证据表明HNF 4也可能在调节细胞周期中发挥作用。为了解决这些问题，我们提出了以下三个具体目标：1）使用基因组规模分析和体内小鼠模型确定HNF 4的新靶基因，以检查HNF 4亚型的功能差异; 2）研究酪氨酸磷酸化在HNF 4功能中的作用; 3）研究HNF 4在调节细胞周期中的作用。拟议的实验将继续使用广泛的现代技术研究HNF 4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。它们还将提供有关与HNF 4有关的各种人类疾病的宝贵信息。最后，作为一个潜在的药物靶点，更全面地了解HNF 4靶向的基因以及靶向HNF 4的信号通路对于开发适当的治疗方法至关重要。 项目叙述：我们的研究与公共卫生有关，因为它试图破译基因在肝脏和肠道中开启的机制。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。