# Chemoproteomic-Enabled Strategy to Study SLC Transporter Roles in Inflammation

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2022 · $685,123

## Abstract

PROJECT SUMMARY
The innate immune system is the first line of defense against invading pathogens and intimately collaborates
with the adaptive immune system to maintain physiological homeostasis. However, components of the immune
response can sometimes become dysfunctional, failing in this protective role and even directly causing a variety
of autoimmune diseases. Immune dysfunction arises from an interplay of genetic and environmental factors,
however a mechanistic understanding of the various proteins and pathways that drive these conditions remains
incomplete. In particular, it is known that immune sensors, which are typically dedicated to protection against
infection, are sometimes usurped, and instead initiate and propagate autoimmune diseases such as systemic
lupus erythematosus (SLE) and Crohn’s disease. Specifically, self-induced signaling by nucleic acid-sensing
endosomal Toll-like receptors (TLRs 7 and 9) and the unchecked production of pro-inflammatory cytokines (e.g.
type I interferons; IFN-I) in plasmacytoid dendritic cells (pDCs) are key events in the pathogenesis of numerous
autoimmune conditions. Thus, compounds that can suppress the production of these cytokines in pDCs would
be clinically useful agents for the treatment of such diseases. Recently, loss-of-function studies of the poorly
characterized endolysosomal solute carrier gene family 15 member 4 (SLC15A4) in lupus mouse models
revealed significantly reduced disease manifestation as well as near complete suppression of TLR7/9-mediated
production of IFN-I and other proinflammatory cytokines. In this application, we have leveraged our lab’s
innovative chemoproteomic fragment-based ligand discovery platform to develop a suite of chemical probes that
engage SLC15A4 in human pDCs, block SLC15A4 mediated transport, and suppress IFN-I production in human
and mouse primary pDCs. We will utilize an interdisciplinary strategy that draws upon the fields of chemical
biology, immunology and mass spectrometry to illuminate how SLC15A4 controls TLR-mediated production of
IFN-I in primary human and mouse immune cells and evaluate pharmacological inhibition in vivo. Specifically,
we will investigate the effects of SLC15A4 pharmacological inhibition on endolysosomal homeostasis, on the
protein interaction network of SLC15A4 and on signaling in immune cells crucial to autoimmune pathophysiology.
Critically, we will assess the therapeutic potential of SLC15A4 in disease models of inflammation, such as lupus.
The chemical tools generated, and knowledge gained from these studies are certain to greatly advance our
understanding of SLC15A4 biology, enabling the identification of novel strategies to treat human autoimmune
diseases.

## Key facts

- **NIH application ID:** 10434128
- **Project number:** 5R01AI156268-03
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Christopher G Parker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $685,123
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434128

## Citation

> US National Institutes of Health, RePORTER application 10434128, Chemoproteomic-Enabled Strategy to Study SLC Transporter Roles in Inflammation (5R01AI156268-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10434128. Licensed CC0.

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