My career goals are to become a physician scientist, caring for children with liver disease and making significant research contributions to the field of Pediatric Hepatology. I have been intrigued with biliary atresia (BA) and its possible mechanisms of pathogenesis since my exposure to this disease in pediatric residency. For the past year, I have been studying immunology in the laboratory of Dr. Stephen Miller, PhD, Northwestern University. I plan to remain in the academic setting long-term as a research scientist with the goal of defining clearly the role of the immune system in the pathogenesis of biliary atresia and other pediatric liver diseases. Biliary atresia is a progressive, inflammatory cholangiopathy of infancy that leads to fibrosis and obliteration of both the extrahepatic and intrahepatic bile ducts. The immune response appears to be the key player in the ongoing destruction of the bile ducts. The hypothesis herein is that the pathogenesis of BA involves a viral induced, progressive autoreactive CD4+ Th1 cell mediated destruction of bile ducts. The group A rotavirus murine model will be used to test this hypothesis and entails a virally induced, progressive inflammatory destruction of extrahepatic and intrahepatic bile ducts leading to extrahepatic ductal fibrosis and obliteration. Limited studies on human liver tissue obtained at the time of diagnosis of BA will also be performed.
Specific Aim 1 will be to characterize the inflammatory immune response in this murine model through the use of immunohistochemistry and flow cytometric studies. Characterization of the cytokine profile will also be performed.
Specific Aim 2 will determine the principal mediator of ductal destruction (virus versus immune response) in the murine model by comparing infected BALB/c pups with infected SCID (immunodeficient) pups.
Specific Aim 3 will determine if autoreactive lymphocytes to bile duct antigens are present in the murine model by performing in-vitro T-cell proliferation studies.
Specific Aim 4 will characterize the inflammatory immune response in human liver tissue obtained at the time of diagnosis of BA with immunohistochemistry studies. Cytokine profiles will be characterized by cytokine mRNA expression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
7K08DK060710-02
Application #
6620592
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2002-08-15
Project End
2006-12-31
Budget Start
2002-08-15
Budget End
2002-12-31
Support Year
2
Fiscal Year
2002
Total Cost
$71,956
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Ng, Vicky L; Sorensen, Lisa G; Alonso, Estella M et al. (2018) Neurodevelopmental Outcome of Young Children with Biliary Atresia and Native Liver: Results from the ChiLDReN Study. J Pediatr 196:139-147.e3
Tucker, Rebecca M; Hendrickson, Richard J; Mukaida, Naofumi et al. (2007) Progressive biliary destruction is independent of a functional tumor necrosis factor-alpha pathway in a rhesus rotavirus-induced murine model of biliary atresia. Viral Immunol 20:34-43
Mack, Cara L; Falta, Michael T; Sullivan, Andrew K et al. (2007) Oligoclonal expansions of CD4+ and CD8+ T-cells in the target organ of patients with biliary atresia. Gastroenterology 133:278-87
Mack, Cara L (2007) The pathogenesis of biliary atresia: evidence for a virus-induced autoimmune disease. Semin Liver Dis 27:233-42
Mack, Cara L; Tucker, Rebecca M; Lu, Brandy R et al. (2006) Cellular and humoral autoimmunity directed at bile duct epithelia in murine biliary atresia. Hepatology 44:1231-9
Mack, Cara L; Tucker, Rebecca M; Sokol, Ronald J et al. (2005) Armed CD4+ Th1 effector cells and activated macrophages participate in bile duct injury in murine biliary atresia. Clin Immunol 115:200-9
Sokol, Ronald J; Mack, Cara L (2005) Optimizing outcomes and bridging biliary atresia into adulthood. Hepatology 41:231-3
Mack, Cara L; Sokol, Ronald J (2005) Unraveling the pathogenesis and etiology of biliary atresia. Pediatr Res 57:87R-94R
Mack, Cara L; Tucker, Rebecca M; Sokol, Ronald J et al. (2004) Biliary atresia is associated with CD4+ Th1 cell-mediated portal tract inflammation. Pediatr Res 56:79-87
Sokol, Ronald J; Mack, Cara; Narkewicz, Michael R et al. (2003) Pathogenesis and outcome of biliary atresia: current concepts. J Pediatr Gastroenterol Nutr 37:4-21