Pathogenesis of Primary Biliary Cholangitis - PROJECT SUMMARY/ABSTRACT
The major goal of this proposal is to conduct the first multi-omics translational study of Primary Biliary
Cholangitis (PBC), thereby identifying the systems-level networks driving pathological processes in this rare,
autoimmune liver disease. Improved understanding of PBC pathogenesis is urgently needed to inform tailored
care and the development of new effective therapies. Comprehensive assessments of immunity and the role of
environmental influence in PBC are currently lacking. Such evaluations would provide critical knowledge to
leverage recent advances in the field’s ability to pharmacologically alter the immune system, thereby providing
new hope to PBC patients. Having made significant contributions to the understanding of the genomic
architecture underlying development of autoimmunity in PBC, we propose a novel, patient-oriented, multi-
omics approach. In this new application, we will decipher how peripheral cellular immunity and non-cellular
circulating factors contribute to PBC pathogenesis. We hypothesize that multi-omic analyses integrating
cellular and non-cellular factors will identify systems-level pathways driving PBC pathogenesis. To test
this hypothesis, we develop an innovative platform that combines aspects of machine learning and quantum
statistical mechanics to identify omics-based signatures of PBC that when integrated with clinical features
will unveil biological pathways driving disease pathogenesis.
To perform this multi-omic study of PBC, we have assembled a world-class, multi-disciplinary team
synergizing expertise in PBC biology and omics-scale analytics as well as resources across Mayo Clinic and
Columbia University. With a new, in-hand collection of diverse biological specimens from 300 deeply-
phenotyped PBC patients and 300 well-matched controls, our studies are already underway with preliminary
data demonstrating measureable immunome, methylome, inflammatory protein, exposome, and metabolome
differences between PBC patients and controls. In Aim 1, we thoroughly evaluate peripheral immune
composition (the immunome) and activation state (methylome, transcriptome, inflammatory proteins) using
mass-cytometry (CyTOF), sequencing- and proximity extension-based methods. In Aim 2, we perform a
cutting-edge study of exogenous chemicals “the exposome” and endogenous metabolites “the metabolome”
using ultrahigh resolution mass spectroscopy to discover pathogenic alterations in metabolism in PBC. We
also develop an assay to quantify liver-specific cell-free DNA in blood as a measure of disease severity. In Aim
3, we integrate omic-specific signatures (Aims 1 and 2) using a novel approach to identify and prioritize PBC-
associated features for further biological investigation. We then infer clinically-relevant subgroups of PBC
patients by performing similarity network fusion analysis. In summary, using state-of-the-art, multi-omic
analyses, we will discover systems-level networks driving PBC pathogenesis, spurring development of new
hypotheses and studies designed to elucidate PBC pathobiology and identify novel therapies.