Fringe Genes as Notch Pathway Modifiers: Role in Bile Duct Growth and Remodeling

边缘基因作为 Notch 通路修饰剂：在胆管生长和重塑中的作用

• 批准号: 8088159
• 负责人: MATTHEW Joseph RYAN
• 金额: $ 14.68万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-20 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8088159
• 关键词: Accounting; Adult; Advisory Committees; Affect; Alagille Syndrome; Area; Biliary; Biological Assay; Blood Vessels; Cardiac; Cell Culture System; Cell Line; Cell surface; Cessation of life; Child; Childhood; Clinical; Collaborations; Controlled Environment; Data; Development; Disease; Employee Strikes; Environment; Exhibits; Family member; Genes; Genetic; Genetic Crosses; Growth; Hepatic; Hepatology; Icterus; Imaging Techniques; In Vitro; Inborn Genetic Diseases; Intrahepatic bile duct; Knowledge; Lead; Learning; Ligands; Liver; Liver diseases; Luciferases; Measurement; Mediator of activation protein; Mentors; Minority; Modification; Molecular; Morbidity - disease rate; Morphogenesis; Mus; Mutation; Notch Signaling Pathway; Pathogenesis; Pathway interactions; Patients; Pattern; Pediatric Hospitals; Pennsylvania; Phenotype; Philadelphia; Physicians; Process; Protein Glycosylation; Regulation; Reporter; Research; Research Personnel; Role; Scientist; Signal Transduction; Syndrome; Time; Training Programs; Universities; bile duct; biliary tract; cholangiocyte; design; experience; glycosylation; glycosyltransferase; human MFNG protein; in vivo; in vivo Model; insight; mouse model; mutant; notch protein; novel; programs; protein transport; receptor; reconstruction; research study; skeletal; skills; symposium

DESCRIPTION (provided by applicant): This application describes a comprehensive training program designed to transition Dr. Ryan from a mentored scientist into an independent investigator in the area of Pediatric Gl and Hepatology studying the role of the Notch signaling pathway in liver and bile duct development. Dedicated sponsors and a carefully chosen research advisory committee will assist and guide Dr. Ryan in this process. The Children's Hospital of Philadelphia and nearby University of Pennsylvania campus provide a fertile learning environment with many investigators on campus studying liver disease and Notch signaling. The environment lends itself to frequent interactions and collaborations. Dr. Ryan's training program will include seminars and conferences as well as a research program designed to allow Dr. Ryan to develop the skills and experience necessary to transition to independence as a physician scientist. Cholestatic liver disease is a significant cause of morbidity and death, yet little is known regarding the molecular regulation of bile duct growth and remodeling. Mouse models and cell culture systems provide excellent means with which to study the mechanisms that control liver and bile duct growth and remodeling. We have discovered a unique phenotype of bile duct proliferation in mice heterozygous for mutations in the Notch pathway ligand, Jag1, and modifier genes, Lunatic fringe (Lfng), Radical fringe (Rfng), and Manic fringe (Mfng). The proposed aims are designed to delineate the time course over which the phenotype develops, analyze Notch receptor-ligand interactions and elucidate the mechanisms underlying the bile duct proliferation. To achieve these aims, we will utilize in vivo mouse models as well as derive primary cholangiocyte cell lines from the double heterozygous mice. Relevance: The data gained from the proposed experiments will contribute to the understanding of bile duct growth and remodeling. This knowledge will potentially lead to directed therapies for cholestatic liver disease in adults and children and insight into the pathogenesis of these disorders.

描述（由申请人提供）： 该应用程序描述了一项全面的培训计划，旨在将瑞安（Ryan）博士从指导的科学家转变为小儿GL领域的独立研究者，并研究了Notch信号通路在肝脏和胆管发展中的作用。专门的赞助商和精心选择的研究咨询委员会将协助和指导Ryan博士参加此过程。费城儿童医院和宾夕法尼亚大学校园附近的校园提供了肥沃的学习环境，许多研究人员在研究肝病和缺口信号的校园里。环境可以频繁地进行交互和协作。瑞安（Ryan）博士的培训计划将包括研讨会和会议，以及旨在允许瑞安（Ryan）博士发展到过渡到独立医师科学家所必需的技能和经验的研究计划。胆固性肝病是发病率和死亡的重要原因，但对于胆管生长和重塑的分子调节而言，知之甚少。小鼠模型和细胞培养系统提供了研究肝脏和胆管生长和重塑的机制的出色手段。我们发现了杂合子中的胆管增殖的独特表型，用于凹槽途径配体，JAG1和修饰剂基因，Lunatic Fringe（LFNG），自由基条纹（RFNG）和Manic Fring（MFNG）中的突变。所提出的目的旨在描述表型开发，分析Notch受体 - 配体相互作用并阐明胆管增殖的基础机制的时间过程。为了实现这些目标，我们将利用体内小鼠模型，并从双杂合小鼠中得出原代胆管细胞细胞系。相关性：从提出的实验中获得的数据将有助于理解胆管生长和重塑。这些知识可能会导致成人和儿童胆汁淤积性肝病的定向疗法，并深入了解这些疾病的发病机理。