Novel gene discovery in disorders of the liver and biliary tree

肝脏和胆管系统疾病的新基因发现

基本信息

批准号：
10370717
负责人：
Alanna Strong
金额：
$ 16.53万
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：
2022
资助国家：
美国
起止时间：
2022-01-19 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10370717
关键词：
Acute Liver Failure Adult Advisory Committees Animal Model Applications Grants Autoimmune Award Biliary Biliary Atresia Biological Assay Candidate Disease Gene Cell Line Cell model Child Child Care Childhood Cholestasis Clinical Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats Code Complex Computerized Medical Record Copy Number Polymorphism Data Defect Development Diagnosis Disease Ethylnitrosourea Etiology Faculty Fellowship Fibrosis Filtration Functional disorder Future Gastroenterology Gene Expression Genes Genetic Genetic Transcription Genomics Goals Grant Hardikar syndrome Hepatic Hepatobiliary Hepatology Human Genetics Immunofluorescence Immunologic Individual Intellectual functioning disability Intestines K-Series Research Career Programs Laboratories Lead Learning Life Literature Liver Liver Dysfunction Liver diseases Mediator of activation protein Medical Genetics Medicine Mentors Messenger RNA Metabolic Microscopy Modeling Morbidity - disease rate Morphology Mutation Notch Signaling Pathway Paper Pathogenesis Pathogenicity Pathway interactions Patients Pattern Pediatric Hospitals Pediatrics Pennsylvania Phenotype Philadelphia Physicians Population Postdoctoral Fellow Proteins RNA Polymerase II Reagent Recording of previous events Reporting Research Research Proposals Residencies Resources Retinal Diseases Role Running Scientist Signal Transduction Standardization Structure Syndrome TGFB1 gene Testing Training Universities Validation Variant Work Writing X-linked intellectual disability Zebrafish beta catenin biliary tract career career development cholangiocyte cleft lip and palate clinical diagnosis cohort congenital hepatic fibrosis design exome exome sequencing experience experimental study gene discovery genetic disorder diagnosis genetic testing genetic variant improved malformation mortality mutant neurogenetics notch protein novel novel therapeutic intervention novel therapeutics pediatric patients professor transcription factor urinary tract obstruction

项目摘要

This career development award details a 5-year training plan to facilitate transition to an independent career as a hepatogeneticist focused on gene discovery and characterization for hepatobiliary disease. I completed my Pediatrics residency at St. Christopher’s Hospital for Children and my fellowship in Human Genetics at The Children’s Hospital of Philadelphia (CHOP). I am currently an attending physician and research fellow at CHOP in the Division Of Human Genetics. My clinical and research efforts focus on children with hepatobiliary disease. My goals for this proposal are to become more experienced with exome and genetic variant interpretation and to gain experience using zebrafish as a model to study hepatobiliary disease. I will also use this opportunity to develop my ability to design experiments, write successful grant applications, and lead a laboratory, to facilitate a smooth transition to academic faculty. My mentor for this proposal is Dr. Hakon Hakonarson, a Professor of Pediatrics and director of the Center for Applied Genomics (CAG) at CHOP. Dr. Hakonarson has mentored dozens of post-doctoral research fellows and K-awardees, and was the recipient of CHOP’s Research Mentor Award. I will be co-mentored by Dr. Michael Pack, a Professor of Medicine at the University of Pennsylvania (UPenn). Dr. Pack also has an extensive history of mentoring trainees and K-awardees and works closely with Dr. Hakonarson on novel gene characterization. I have also assembled a scientific advisory committee, consisting of Drs. Klaus Kaestner, Ben Stanger, Kirk Wangensteen, Tom Jongens, and Elizabeth Rand, all experts in the fields of hepatology, neurogenetics or genetics with extensive mentoring experience. I will also have the benefit of the outstanding resources at both CHOP and UPenn, which have facilitated career development for countless past trainees. My proposed research focusses on the discovery and characterization of novel genes implicated in hepatobiliary disease. We are assembling a cohort of individuals with unexplained hepatobiliary disease, and will apply a research pipeline to facilitate identification of novel genes. Our laboratory has already identified de novo nonsense and frameshift variants in MED12 as causal for Hardikar Syndrome, a syndromic form of biliary dysgenesis, of previously unknown genetic basis. Aim 1 of this proposal delineates how a patient cohort will be assembled and characterized, and Aim 2 details the characterization of the role of MED12 in biliary development. Completion of the proposed studies will improve our ability to genetically diagnose hepatobiliary disease, better characterize the genetic landscape of these poorly-understood conditions, and elucidate the mechanism by which nonsense and frameshift MED12 variants cause biliary disease. This proposal will also provide me with experience studying hepatobiliary disease in animal and cellular models, writing grants and scientific papers, and allow me to observe how academic laboratories are run. Furthermore, this patient cohort and the cellular and animal models developed as part of this proposal will be invaluable in my future career.

该职业发展奖详细介绍了一项为期5年的培训计划，以促进过渡到独立职业肝发育家着重于肝疾病的基因发现和表征。我完成了圣克里斯托弗儿童医院的儿科住所和我的人类遗传学研究金费城儿童医院（CHOP）。我目前是Chop的身体和研究员在人类遗传学的划分中。我的临床和研究工作集中于患有肝疾病的儿童。我的这一建议的目标是通过外显子和遗传变异的解释变得更有经验以利用斑马鱼作为研究肝病疾病的模型的经验。我还将利用这个机会发展我设计实验，编写成功的赠款应用程序并领导实验室的能力，以促进向学术教师的平稳过渡。我对这项建议的精神是Hakon Hakonarson博士，儿科教授兼中心主任Hakon Hakonarson博士 Chop的应用基因组学（CAG）。 Hakonarson博士指导了数十名博士后研究研究员和 K-Awardees，并获得了CHOP研究导师奖。我将由迈克尔博士共同出庭 Pack，宾夕法尼亚大学（UPENN）的医学教授。 Pack博士也有悠久的历史心理学员和K-awardees的成员，并与Hakonarson博士紧密合作进行了新的基因表征。我还组建了一个由Drs组成的科学咨询委员会。 Klaus Kaestner，Ben Stanger，Kirk Wangensteen，Tom Jongens和Elizabeth Rand，肝病学领域的所有专家具有丰富心理经验的遗传学。我还将在这两个方面都有杰出资源的好处 Chop and Upenn为无数学员准备了职业发展。我拟议的研究重点是在肝动物中实现的新基因的发现和表征疾病。我们正在组装一群患有意外肝病的人，并将应用研究管道促进新基因的鉴定。我们的实验室已经确定 Med12中的胡说八道和移交变体作为Hardikar综合征的因果关系，这是一种胆汁综合征的形式失去障碍，以前未知的遗传基础。该提案的目标1描述了患者队列的方式组装和表征，目标2详细介绍了Med12在胆道发育中的作用的表征。拟议研究的完成将提高我们遗传诊断肝疾病的能力，更好表征这些不良理解条件的遗传景观，并通过这是胡说八道和移状Med12变体引起胆道疾病。该建议还将为我提供在动物和细胞模型中研究肝胆疾病，撰写赠款和科学论文的经验，并允许我观察如何运行学术实验室。此外，该患者队列和细胞作为该提案的一部分开发的动物模型将在我未来的职业生涯中无价。