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Differential role of TASL and SLC15A4 in TLR responses to nucleic acids and lupus development

Award Number: R21AI174237
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Systemic lupus erythematosus (SLE) is characterized by hyperactivation of T cells, B cells and dendritic cells (DCs), production of autoantibodies to nucleic acid-associated and other self-molecules, and immune complex-mediated inflammatory damage in multiple organs. Mechanistic assessments in both mouse models and humans have implicated innate immune pathways of nucleic acid sensing in lupus pathogenesis, particularly Toll-like receptor (TLR) activation in B cells and plasmacytoid dendritic cells (pDCs), production of type I interferons, and expression of an interferon-inducible gene signature often correlating with disease activity. Additional studies including by our laboratory have shown that pathogenic TLR responses in systemic autoimmunity require the participation of the peptide/histidine transporter SLC15A4, suggesting that inhibition of this transporter may be an effective therapeutic approach. Very recent studies, however, suggested that SLC15A4 does not act as a transporter but rather as binding partner of TASL, which in turn facilitates TLR signaling. Thus, the focus of this proposal is to define mechanistically how SLC15A4 and TASL contribute to TLR activation. For this we will use a novel TASL- deficient mouse model that will allow to separate the SLC15A4 role as a transporter vs. its role as a platform that facilitates recruitment of TASL. Crucially, these studies will clarify if pharmacologic inhibition of the SLC15A4 transporter activity is an appropriate strategy, or if instead targeting TASL would be a better approach to reduce inflammatory responses in lupus and other autoimmune conditions.


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: 2024 ( Subtotal = $240,000 )
2024	2024	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT STE 200	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	2	5/9/2024	NON-COMPETING CONTINUATION	$24,000
2024	2024	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT STE 200	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	10/25/2023	NON-COMPETING CONTINUATION	$216,000
														Subtotal = $240,000

Issue Date FY: 2023 ( Subtotal = $288,000 )
2023	2023	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	11/18/2022	NEW	$288,000
														Subtotal = $288,000

Grand Total All Awards = $528,000

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Differential role of TASL and SLC15A4 in TLR responses to nucleic acids and lupus development

Award Number: R21AI174237

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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