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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.

这个职业发展奖励详细说明了一个5年的培训计划，以促进过渡到独立的职业生涯