Role of Uhrf1 in Liver Development, Regeneration and Carciogenesis

Uhrf1 在肝脏发育、再生和癌变中的作用

基本信息

批准号：
7911284
负责人：
Kirsten C Sadler Edepli
金额：
$ 9.99万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7911284
关键词：
Address Adult Apoptosis Biochemical Biochemistry Biological Cancer Biology Cancer cell line Carcinogens Cell Culture Techniques Cell Cycle Cell Proliferation Cell division Cells Chronic Clinical Cultured Cells Cyclin A DNA Methylation Regulation DNA Methyltransferase DNA Modification Methylases DNA-Binding Proteins Data Development Disease Embryo Embryonic Development Event Fingers Fishes Gene Dosage Gene Targeting Genes Genetic Genetic Programming Genetic Screening Goals Growth Hepatic Hepatocarcinogenesis Hepatocyte Human Human Biology Human Genetics In Vitro Injection of therapeutic agent Injury Link Liver Liver Regeneration Liver diseases Liver neoplasms Malignant Neoplasms Malignant neoplasm of liver Mammalian Cell Mammals Mediating Modeling Natural regeneration Oncogenes Oncogenic Partial Hepatectomy Pathologic Pathway interactions Patient Care Patients Phenotype Phosphorylation Physiological Play Predisposition Primary carcinoma of the liver cells Process Property Protein Binding Publishing Regulation Role Sampling Suggestion System TOP2A gene Techniques Tertiary Protein Structure Testing Topoisomerase Transcript Transcription Coactivator Transgenic Organisms Ubiquitin Up-Regulation Work Zebrafish cancer genomics cell transformation chemotherapeutic agent cohort cost effective cyclin A2 fatty acid-binding proteins human CDK2 protein human HDAC1 protein in vivo interest knock-down liver cell proliferation loss of function mutation mimetics mutant novel promoter public health relevance response tissue culture tumor tumorigenesis ubiquitin-protein ligase zebrafish development

项目摘要

DESCRIPTION (provided by applicant): Liver development in embryos and regeneration in adults are characterized by regulated hepatocyte proliferation. This contrasts with the unregulated hepatocyte proliferation that accompanies many chronic hepatic diseases and hepatocellular carcinoma (HCC). While there is suggestion that common genetic pathways regulate both physiologic and pathologic hepatocyte proliferation, only a few studies in mammals illustrate this hypothesis. By forward genetic screening in zebrafish embryos combined with functional studies on liver regeneration in adults and expression analysis of human HCC samples, we have found that the ubiquitin-like, containing PHD and RING finger domains-1 (uhrf1) gene is essential for physiologic hepatocyte proliferation. We also believe that alterations in UHRF1 expression and/or regulation also contribute to deregulated proliferation in cancer. The work in this proposal will use a combination of zebrafish development and genetics, human cancer genomic analysis and mammalian tissue culture cell cycle studies and biochemistry to address 3 aspects of UHRF1 function in relation to hepatocyte proliferation. In Specific Aim 1, we will examine the mechanism by which UHRF1 functions in regulating hepatocyte proliferation in zebrafish embryos. In Specific Aim 2, we will elucidate how UHRF1 is regulated through phosphorylation by cyclin dependent kinase 2. The functional relevance of this phosphorylation will be assessed on cultured cells using biochemical and cell biological techniques. In Specific Aim 3, we will determine the role of UHRF1 in hepatocarcinogenesis. By analysis of human HCC samples, we will evaluate the possibility that amplification of the UHRF1 locus contributes to its upregulation in cancer. Secondly, we will perform genetic and oncogenic studies in zebrafish and determine if UHRF1 is necessary and sufficient for hepatic tumor formation. In summary, this proposal will link together mechanisms that control hepatocyte proliferation in the embryo and during liver regeneration with those that control hepatocarcinogenesis. This proposal has direct relevance to the field of liver disease. Because the burden of liver disease remains enormous, the identification of genes that play critical roles in hepatocyte proliferation and in HCC progression are of significant scientific and clinical importance. The goal is to identify novel mechanisms of hepatocyte proliferation that can aid in the development of chemotherapeutic agents for use in management of patients with chronic liver diseases including HCC. PUBLIC HEALTH RELEVANCE: We are interested in how the liver develops, how it restores itself after injury and how liver cancer occurs. We believe that all three processes are linked and that understanding of normal liver growth will help in caring for patients with liver cancer. We believe that we have discovered a gene called UHRF1 that is involved in all the three processes and will study how it plays a role in each situation. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page

描述（申请人提供）：胚胎中的肝发育和成人再生的特征是受调节的肝细胞增殖。这与许多慢性肝疾病和肝细胞癌（HCC）伴随的不受管制的肝细胞增殖形成对比。尽管有建议，常见的遗传途径调节生理和病理性肝细胞增殖，但哺乳动物中只有少数研究说明了这一假设。通过在斑马鱼胚胎中进行正向遗传筛查，结合了成人肝脏再生的功能研究和人类HCC样品的表达分析，我们发现含有泛素样的泛素样，含有PHD和RING FINGE域-1（UHRF1）基因是生理性肝细胞增殖的必不可少的。我们还认为，UHRF1表达和/或调节的改变也有助于癌症中的扩散。该提案中的工作将结合斑马鱼发育和遗传学，人类癌基因组分析和哺乳动物组织培养细胞周期研究和生物化学来解决UHRF1功能与肝细胞增殖有关的三个方面。在特定目标1中，我们将研究UHRF1在调节斑马鱼胚胎中调节肝细胞增殖的机制。在特定目标2中，我们将通过细胞周期蛋白依赖性激酶2阐明如何通过磷酸化来调节UHRF1。该磷酸化的功能相关性将使用生化和细胞生物学技术在培养细胞上评估。在特定的目标3中，我们将确定UHRF1在肝癌发生中的作用。通过对人类HCC样品的分析，我们将评估UHRF1基因座的扩增有助于其在癌症中的上调的可能性。其次，我们将在斑马鱼中进行遗传和致癌研究，并确定UHRF1是否需要肝肿瘤形成。总而言之，该提案将将控制胚胎中肝细胞增殖和肝脏再生期间的机制与控制肝癌发生的机制联系起来。该提案与肝病领域有直接相关的意义。由于肝病的负担仍然很大，因此鉴定在肝细胞增殖和HCC进展中起着关键作用的基因具有重要的科学和临床重要性。目的是确定肝细胞增殖的新型机制，这些机制可以帮助开发化学治疗剂，以用于治疗包括HCC在内的慢性肝病患者。公共卫生相关性：我们对肝脏的发展方式，受伤后如何恢复自身以及肝癌的发生感兴趣。我们认为，这三个过程都是联系在一起的，对正常肝脏生长的理解将有助于照顾肝癌患者。我们认为，我们发现了一个称为UHRF1的基因，该基因参与了所有这三个过程，并将研究它在每种情况下的作用。 PHS 398/2590（修订版09/04，重新发行4/2006）页面延续格式页面