Role of Cirhin/Utp4 in biliary development and disease

Cirhin/Utp4 在胆道发育和疾病中的作用

基本信息

批准号：
9064761
负责人：
Benjamin J Wilkins
金额：
$ 14.23万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9064761
关键词：
Address Affect Affinity Chromatography Anatomy Animal Model Basic Science Biliary Biliary cirrhosis Biogenesis Biological Models Birth Caring Cell Communication Cell Proliferation Cell physiology Cells Cessation of life Childhood Cholestasis Cirrhosis Clinical Complement Congenital atresia of extrahepatic bile duct Cultured Cells Data Development Diagnosis Discipline Disease Doctor of Medicine Doctor of Philosophy Environment Etiology Extrahepatic Fellowship Fetal Development Fishes Fostering Functional disorder Gastrointestinal Diseases Gene Targeting Genes Growth Health Hepatocyte Histologic Homologous Gene Human Hyperbilirubinemia Icterus In Vitro Laboratories Lead Life Liver Liver Fibrosis Liver diseases Malignant Neoplasms Mammals Mentors Mentorship Methods Missense Mutation Modeling Molecular Mutate Mutation North American Indians Nucleolar Proteins Oligonucleotides Pathogenesis Pathologist Pathology Pathway interactions Patients Pediatric Hospitals Pennsylvania Peptides Phenotype Philadelphia Physicians Population Predisposition Principal Investigator Program Development Publishing Quebec RNA Processing Research Research Personnel Residencies Ribosomal RNA Ribosomes Role Scientist Series Single-Gene Defect System TP53 gene Technology Testing Tissues Training Training Programs Transcription Coactivator Transgenic Organisms Translating Universities Yeasts Zebrafish bile duct biliary tract career career development cell type cytopenia developmental genetics disease-causing mutation experience gastrointestinal improved in vivo in vivo Model infancy insight interest liver biopsy liver development liver injury meetings member mutant novel nuclease programs research and development research study spatiotemporal therapeutic target transcription activator-like effector nucleases transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): This proposal describes a five year training program for development of a career in basic research and academic pediatric pathology. The principal investigator has completed a combined M.D./Ph.D. program, residency and fellowship training in anatomic and pediatric pathology, and 2 years of postdoctoral research. The training period will allow for development of an independent research program, as well as provide experience as an independently-practicing pediatric pathologist focusing on the diagnosis of pediatric gastrointestinal and liver disease. Research during the training program will focus on the attainment of expertise in studying the pathophysiology of pediatric liver disease through in vivo modeling in zebrafish. The zebrafish system provides many of the advantages of classical genetic and developmental models, combined with the vertebrate body plan of mammals, and has been validated as a model system for liver development and disease. Research will be performed under the mentorship of Dr. Michael Pack at the University of Pennsylvania, an expert in zebrafish models of gastrointestinal development and disease, as well as a mentoring committee of outstanding physician-scientists with expertise in zebrafish models, biliary disease, and the training of young physician-scientists. Infantile cholestasis is caused by numerous etiologies, many of which are rare single-gene defects that affect biliary development or function. Study of the genes involved in these cholangiopathies through animal modeling often leads to further understanding of both normal liver development, as well as the pathophysiologic mechanisms that lead to disease. One such gene is CIRH1A/hUTP4, mutated in North American Indian Childhood Cirrhosis (NAIC), a disease that presents clinically and histologically as obstructive cholestasis but with an intact biliary tree. CIRH1A is unique among genes involved in cholangiopathies, in that it encodes a nucleolar protein (CIRHIN) that functions in ribosome biogenesis, as demonstrated by prior in vitro experiments. The role of ribosome biogenesis in biliary development is unknown. The research plan will utilize transgenic and gene-targeting methods in zebrafish to test the hypothesis that Cirhin is necessary for normal biliary development and function. The specific aims include: 1) Generate zebrafish models of cirh1a inhibition to investigate the pathophysiologic mechanism of NAIC, and 2) Determine the mechanism of Cirhin action; specifically, investigate the role of Nol11/Cirhin interactions in biliary development. These studies will provide the first in vivo models for studying Cirhin function, and the first animal models of NAIC. In addition, molecular mechanisms for NAIC pathogenesis uncovered by these models will also be more broadly applicable to other diseases caused by ribosomal dysfunction ("ribosomopathies"). The Children's Hospital of Philadelphia (CHOP) provides an excellent venue for developing expertise in pediatric liver disease. CHOP is a world leader in pediatric disease care and research. The Biesecker Center for Pediatric Liver Disease brings together clinicians and researchers from numerous disciplines at CHOP and the University of Pennsylvania to promote the study of a variety of developmental liver disorders. The Division of Anatomic Pathology at CHOP is a supportive training environment, and has a clinical expertise in the diagnosis of pediatric gastrointestinal and liver disease. Interaction wih colleagues, in both local forums and national meetings, will complement the proposed research and career development program to foster development of an independent academic career.

描述（由申请人提供）：该提案描述了一个为期五年的培训计划，旨在发展基础研究和学术儿科病理学的职业生涯。主要研究者已完成医学博士/博士学位。解剖学和儿科病理学项目、住院医师和研究员培训，以及 2 年博士后研究。培训期间将允许开发独立的研究计划，并提供作为独立执业的儿科病理学家的经验，专注于儿科胃肠道和肝脏疾病的诊断。培训计划期间的研究将侧重于通过斑马鱼体内建模获得研究小儿肝病病理生理学的专业知识。斑马鱼系统提供了经典遗传和发育模型的许多优点，并与哺乳动物的脊椎动物身体计划相结合，并已被验证为肝脏发育和疾病的模型系统。研究将在宾夕法尼亚大学 Michael Pack 博士的指导下进行，Michael Pack 博士是胃肠道发育和疾病斑马鱼模型方面的专家，以及由在斑马鱼模型、胆道疾病和疾病方面具有专业知识的杰出医师科学家组成的指导委员会。年轻医师科学家的培训。婴儿胆汁淤积由多种病因引起，其中许多是影响胆道发育或功能的罕见单基因缺陷。通过动物模型研究参与这些胆管病的基因通常可以进一步了解正常肝脏发育以及导致疾病的病理生理机制。其中一个基因是 CIRH1A/hUTP4，它在北美印第安儿童肝硬化 (NAIC) 中发生突变，这种疾病在临床和组织学上表现为阻塞性胆汁淤积，但胆道树完整。 CIRH1A 在与胆管病相关的基因中是独特的，因为它编码一种核仁蛋白 (CIRHIN)，该蛋白在核糖体生物发生中发挥作用，正如之前的体外实验所证明的那样。核糖体生物发生在胆道发育中的作用尚不清楚。该研究计划将利用斑马鱼的转基因和基因靶向方法来检验 Cirhin 对于正常胆道发育和功能所必需的假设。具体目标包括：1）建立cirh1a抑制斑马鱼模型以研究NAIC的病理生理机制；2）确定Cirhin作用机制；具体而言，研究 Nol11/Cirhin 相互作用在胆道发育中的作用。这些研究将提供第一个用于研究 Cirhin 功能的体内模型，以及第一个 NAIC 的动物模型。此外，这些模型揭示的NAIC发病机制的分子机制也将更广泛地适用于核糖体功能障碍（“核糖体病”）引起的其他疾病。费城儿童医院 (CHOP) 为培养儿科肝病专业知识提供了绝佳的场所。 CHOP 是儿科疾病护理和研究领域的世界领先者。 Biesecker 小儿肝病中心汇集了来自 CHOP 和宾夕法尼亚大学多个学科的临床医生和研究人员，以促进各种发育性肝病的研究。 CHOP 解剖病理学部门拥有支持性培训环境，在儿科胃肠道和肝脏疾病的诊断方面拥有临床专业知识。在当地论坛和全国会议上与同事的互动将补充拟议的研究和职业发展计划，以促进独立学术职业的发展。