Archived record · Edyssy 2014
Isolation, Identification And Characterization Of A Toxin Causing Biliary Atresia
- Agency
- NIHNational Institutes of Health
- Principal investigator
- Michael Pack
- Institution
- University of Pennsylvania
- Amount listed
- $489,444
- Period
- Aug. 1, 2013 to July 31, 2014
Abstract
DESCRIPTION (provided by applicant): Biliary atresia (BA) is a fibro inflammatory disorder that is the leading cause of neonatal cholestasis and the most common indication for liver transplant in the pediatric population. Although epidemiologic data suggest that BA arises from the interplay of genetic risk factors coupled with environmental exposures, the etiology is unknown. Animal models are limited, and the best-known animal model of the disease, the infection of newborn BALB/c mice with rhesus rotavirus (RRV), has provided important information about immunological aspects of the disease but has been less useful for studying the rapidly progressive fibrosis characteristic of the disease. Insight into the pathogenesis of BA comes from the study of a naturally-occurring animal model of the disease. Over the last 40 years, there have been three epidemics of BA in newborn livestock in Australia associated with ingestion of the plant Dysphania glomulifera by pregnant sheep and cows. Clinical and pathological findings from the affected lambs and calves show striking similarities with human BA, in particular marked fibrosis at the time of diagnosis. We hypothesize that determining the causative toxin will enable the identification of general cholangiocyte damage pathways that lead ultimately to BA and fibrosis in vertebrates. We have thus collected and imported D. glomulifera from the Australian pasture affected by the most recent epidemic and have employed a zebrafish bioassay to successively subfractionate the plant and identify active fractions. We have several fractions with a complexity of 2-20 that, remarkably, cause a BA-like pattern of injury (with atresia of the gallbladder and extrahepatic biliary tree) in zebrafish larvae exposed after biliary morphogenesis has occurred, mimicking human BA. The overall goal of this proposal is therefore to identify the biliary toxins in Dysphania, characterize the cholangiocyte damage pathways they induce, and establish new animal models as a means of understanding the pathogenesis of human BA. This will be achieved through three specific aims: 1. to identify D. glomulifera biliary toxins using the in vivo zebrafish bioassay~ 2. To identify molecular markers and genes that regulate extrahepatic biliary injury in zebrafish larvae treated with D. glomulifera toxins~ and 3. To identify and characterize damage pathways induced by D. glomulifera toxins in mammalian models. Public Health Relevance Statement: The goal of this proposal is to identify the toxins in the plant Dysphania glomulifera that are responsible for biliary atresia in livestock. Biliary artesian is a major but poorly understood liver disease in the pediatric population. Dysphania toxins will be used to develop new models of biliary atresia, including models in zebrafish and mice, and to identify the toxin-induced signaling pathways in cells that are damaged in biliary atresia. The goal of this proposal is to identify the toxins in the plant Dysphania glomulifera that are responsible for biliary atresia in livestock. Biliary artesian is a major but poorly understood liver disease in the pediatric population. Dysphania toxins will be used to develop new models of biliary atresia, including models in zebrafish and mice, and to identify the toxin-induced signaling pathways in cells that are damaged in biliary atresia. Affect;Animal Disease Models;Animal Model;Animals;Australia;Biliary;Biliary Atresia;biliary tract;Biological;Biological Assay;Biological Models;Biopsy;Cattle;Cell Culture Techniques;cell injury;Cells;Childhood;cholangiocyte;Cholestasis;Cirrhosis;Clinical;Coculture Techniques;Complex;Coupled;Diagnosis;Disease;disease characteristic;Employee Strikes;Environment;Environmental Exposure;Epidemic;epidemiologic data;Etiology;Event;Extrahepatic;Fibrosis;Gallbladder;Genes;genetic risk factor;Goals;high throughput screening;Human;human disease;in vitro Model;in vivo;in vivo Model;Inbred BALB C Mice;Individual;Infection;Inflammatory;Ingestion;Injury;insight;International;intrahepatic;knock-down;Larva;Lead;Link;Liver;Liver diseases;liver transplantation;Livestock;Macaca mulatta;mature animal;Modeling;molecular marker;Morphogenesis;Mouse Strains;Mus;Myofibroblast;Nature;Neonatal;Newborn Infant;Obstruction;offspring;Orthologous Gene;overexpression;Pathogenesis;Pathway interactions;Patients;Pattern;Phenotype;Plants;Population;precursor cell;pregnant;Pregnant Women;Reporter;research study;Rodent;Rotavirus;Sheep;Signal Pathway;Specimen;Staging;Study models;Time;Tissues;Toxin;Transgenic Organisms;Vertebrates;Viral;Zebrafish
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The record names Michael Pack at University of Pennsylvania as principal investigator. When a professor holds an award like this, part of the budget usually goes to people: graduate research assistants, a postdoc or a technician. Shorter awards are often one year of a renewing project, so check whether it was continued. Look up the investigator’s current awards before you write; a 2014 record is a lead, not a promise. Before you do, read up on what principal investigators look for in a student.
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