# Dissecting the pathogenesis and outcomes of PSC using multi-omics by studying the exposome and genome

> **NIH NIH RC2** · MAYO CLINIC ROCHESTER · 2020 · $1,547,338

## Abstract

PROJECT SUMMARY/ABSTRACT
 The major goal of this RC2 proposal is to generate the first, multi-omics translational study capturing the
sum of environmental exposures (i.e. the exposome) and comprehensive data resource for Primary
Sclerosing Cholangitis (PSC), a chronic, progressive liver disease without effective medical therapy. PSC
shortens survival, is associated with inflammatory bowel disease (IBD) and strongly predisposes to
cholangiocarcinoma (i.e. bile duct cancer) and colon cancer. Our recent genome wide association studies
(GWAS) revealed the significant role of genetic variation in PSC, while also re-emphasizing the importance of
environmental factors and gene-environment interactions in PSC pathogenesis. To further elucidate the role of
exposures from our external environment and lifestyle (e.g., diet, stress, toxins, drugs, microbes), we have
assembled a world-class, multi-disciplinary team that synergizes expertise and resources across four
institutions: Mayo Clinic, Emory University, University of Illinois Urbana-Champaign (UIUC), and
University of Oslo, Norway. Our collaborative team will leverage large clinical databases and biorepositories,
as well as expertise in PSC and related conditions, exposomics, metabolomics, methylomics, transcriptomics,
metagenomics, genomics, and data analytics to develop the PSC Scientific Community Resource for
hypothesis-generating science and simultaneously uncover factors contributing to PSC.
 We now seek to define the bigger-picture cellular networks, rather than individual genes, driving disease
processes. To do so, we will use unbiased network-based approaches designed to integrate multiple layers of
omics data. Our proposal is predicated on the hypothesis that multi-omics analyses of data capturing
environmental exposures and the associated biological responses, including the effect on the genome, will
reveal networks or pathways influencing PSC pathogenesis and outcomes. To test this hypothesis, we will
perform a series of sophisticated analyses to identify PSC-associated changes in and across the exposome,
metabolome, methylome, and transcriptome in blood as well as the gut metagenome, exposome and
metabolome.
 Our collaboration and data generation are already underway with pilot studies demonstrating
differences in blood exposomes and metabolomes and stool metagenomes between PSC patients and
controls. Using a suite of bioinformatic tools and available genetic variation data, we aim to discover stable,
detectable, omics-based disease signatures in blood (Aim 1) and stool (Aim 2) that when integrated with
clinical data (Aim 3) will reveal biological pathways driving disease pathogenesis and outcomes. All data,
residual specimens, and analytical details will be made freely available to the research community in
accordance with NIDDK's mission. Furthermore, this effort responds to the NIDDK's call “to better
understand the role of the microbiome, genetics, and exposome.”

## Key facts

- **NIH application ID:** 9986790
- **Project number:** 5RC2DK118619-03
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** KONSTANTINOS N LAZARIDIS
- **Activity code:** RC2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,547,338
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986790

## Citation

> US National Institutes of Health, RePORTER application 9986790, Dissecting the pathogenesis and outcomes of PSC using multi-omics by studying the exposome and genome (5RC2DK118619-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9986790. Licensed CC0.

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