# Molecular characterization of the role of RNASET2 in Severe Crohn's Disease

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2020 · $375,750

## Abstract

PROJECT SUMMARY/ABSTRACT
Clinical and genetic heterogeneity among the inflammatory bowel diseases (IBD) suggests that IBD is inclusive
of a spectrum of mucosal inflammatory diseases. Predicting disease natural history and development of
subgroup-specific treatment plans are confounded by profound genetic and patho-biologic heterogeneity, but is
essential to the development of targeted therapies. Drug development in unselected patient populations has
had only limited success. Novel approaches are needed to define the distinct patient subpopulations likely to
benefit from new treatments based on precisely selected targets. Ribonuclease T2, (RNASET2) has been
identified as a potential IBD risk gene. Clinically, RNASET2 disease risk variants are associated in CD with a
more complicated/resistant disease phenotype defined in part by therapeutic drug failure, increase in length of
intestinal resection, a shorter time to reoperation and post-operative endoscopy with high scores in
inflammation indices. Recent data demonstrate a functional and biological relationship between RNASET2 and
two additional genes, TNFSF15 and ICAM1, which have been implicated by GWAS as potentially involved in
IBD pathogenesis. Motif screening of RNASET2 disease risk variants identified rs2149092 as a potential
regulatory single nucleotide polymorphism (SNP) predicted to disrupt a consensus ETS-transcription factor
(TF) binding site located within an enhancer region. The hypothesis to be addressed in this proposal is that
identifying the regulatory mechanisms and molecular components comprising TL1A-mediated down-regulation
of RNASET2 expression, and the molecular events contributing to enhancement of pro-inflammatory cytokine
expression/secretion related to decreased levels of RNASET2 and subsequent enhanced ICAM1 expression,
will yield a more precisely defined molecular signature of a severe form of CD as well as potential targets, that
may then be used alone or in combination to optimally mitigate severe disease development in a defined
subset of patients with Crohn’s disease (CD). We will approach this hypothesis by the following Specific Aims.
1) Determine the candidate regulatory variants and cis-and trans-regulatory pathways involved in TL1A
mediated inhibition of RNASET2 expression 2) Determine the cellular and molecular pathways by which
decreased RNASET2 expression drives enhanced LFA1/ICAM1 interaction and subsequent IFNg secretion. 3)
Validate the functional impact of the findings from Specific Aims 1 and 2 by: a) using allele specific expression
of RNASET2 risk variants in T cells isolated from CD patients and b) testing candidate therapeutic targets in
mouse models of TL1A overexpression with many of the characteristics associated with CD to more precisely
define molecular signatures and further refine potential therapeutic targets for severe disease.

## Key facts

- **NIH application ID:** 10021036
- **Project number:** 5R01DK117893-02
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Stephan R. Targan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $375,750
- **Award type:** 5
- **Project period:** 2019-09-19 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10021036

## Citation

> US National Institutes of Health, RePORTER application 10021036, Molecular characterization of the role of RNASET2 in Severe Crohn's Disease (5R01DK117893-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10021036. Licensed CC0.

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