Molecular mechanisms of T cell dysfunction in pediatric chronic cholestatic liver diseases

PROJECT SUMMARY/ABSTRACT
This proposal details a comprehensive five-year training program investigating mechanisms of immune
dysfunction in children with chronic cholestatic liver diseases (CSLD). These diseases are characterized by
accumulation of bile acids in circulation and are the leading indication for liver transplantation (LT) in children.
Infections cause significant morbidity and mortality in children with chronic liver diseases both pre-and post-LT.
Dysregulated immune responses, which can be seen in cirrhosis associated immune dysfunction (CAID),
represent a central driving force in infectious susceptibility and outcomes. However, the molecular basis of
pediatric CAID remains unknown. Bile acids act as signaling molecules by binding to nuclear and cell surface
receptors, playing a key role in immune regulation. Our preliminary studies, consistent with published reports,
show that elevated levels of certain bile acids impair T cell proliferation in in vitro cultures. Further, preliminary
studies from our pediatric cohort and mouse models show poor cytokine expression and impaired T cell
proliferation in CSLD. Thus, our central hypothesis is that in children with chronic CSLD, bile acids act via the
nuclear receptor VDR to transcriptionally repress genes involved in IFN-Ȗ SURGXFWLRQ OHDGLQJ WR LPSDLUHG 7 FHOO
function, thereby causing pediatric CAID. To evaluate this hypothesis, we have formulated the following two
distinct aims: (1) Determine the association between T cell functional deficits, viral infection and severity of
cholestasis in children and in murine models of CSLD. (2) Determine the mechanism by which bile acids regulate
T cell signaling in CSLD. I will use peripheral blood and plasma from children undergoing LT, two mouse models
of cholestasis, and in vitro cell cultures with bile acids in these aims. Our expected outcome is to uncover new
mechanisms of T cell dysfunction in cholestasis, which will ultimately lead to improved overall outcomes in CSLD.
This work will be foundational to achieve my long-term goal of being an independent physician-scientist who
develops therapies to mitigate the consequences of immune dysfunction in CSLD. The proposed experiments
and didactic work will position me with a unique set of cross disciplinary skills that will enable my transition to
independence as a physician scientist. I will be mentored by Dr. Benjamin Shneider, a leader in translational
investigations of pediatric CSLD. I will be co-mentored by Dr. Farrah Kheradmand, an expert in the mechanisms
of immune dysfunction in chronic diseases and Dr. Xian Li, a T cell biology expert. I will expand my translational
research skills with training in T cell signaling, bile acid, and nuclear receptor biology. By leveraging integration
of transcriptomic and metabolomic data using bioinformatic tools (Dr. Cristian Coarfa), I aim to gain a better
understanding of immune deficits in CSLD and translate findings into improved patient care. This integrated
approach is crucial for addressing clinical challenges associated with infections in children with liver disease. My
training plan at a premiere academic research institution will provide knowledge and skills to make substantial
contributions towards identifying and modifying risk factors of immune dysfunction in pediatric liver diseases.