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Chemoproteomic-Enabled Strategy to Study SLC Transporter Roles in Inflammation

Award Number: R01AI156268
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $696,479 )
2025	2025	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	6	6/18/2025	NON-COMPETING CONTINUATION	$696,479
														Subtotal = $696,479

Issue Date FY: 2024 ( Subtotal = $685,123 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	5	6/18/2024	NON-COMPETING CONTINUATION	$685,123
														Subtotal = $685,123

Issue Date FY: 2023 ( Subtotal = $685,123 )
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	4	6/21/2023	NON-COMPETING CONTINUATION	$685,123
														Subtotal = $685,123

Issue Date FY: 2022 ( Subtotal = $668,419 )
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	003	3	8/18/2022	NON-COMPETING CONTINUATION	$685,123
2022	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Allergy and Infectious Diseases Research	002	1	8/17/2022	NEW	$0
2022	2021	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	2	6/17/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$395,321
2022	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Allergy and Infectious Diseases Research	000	1	6/17/2022	NEW	-$412,025
														Subtotal = $668,419

Issue Date FY: 2021 ( Subtotal = $584,460 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Allergy and Infectious Diseases Research	000	1	6/17/2021	NEW	$584,460
														Subtotal = $584,460

Grand Total All Awards = $3,319,604

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Chemoproteomic-Enabled Strategy to Study SLC Transporter Roles in Inflammation

Award Number: R01AI156268

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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