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 i nclude: 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 with 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.
Many childhood liver diseases are caused by mutations that lead to defective bile duct development or function, either during fetal development or early post-natal life. Study of these mutations in animal models improves understanding of how these mutations cause disease, and suggests possible treatments.
|Chandramouleeswaran, Prasanna M; Shen, Dawen; Lee, Anna J et al. (2016) Preferential Secretion of Thymic Stromal Lymphopoietin (TSLP) by Terminally Differentiated Esophageal Epithelial Cells: Relevance to Eosinophilic Esophagitis (EoE). PLoS One 11:e0150968|