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Structure, pharmacology and signaling of G protein-coupled receptors (GPCRs) in inflammation

Award Number: R35GM128641
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2018
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Structure, pharmacology and signaling of G protein-coupled receptors (GPCRs) in inflammation - Project Summary Inflammation is a complex process with many lipid and peptide mediators involved. A large number of these mediators elicit either pro-inflammatory or pro-resolving effects through the action on G protein-coupled receptors (GPCRs). My lab is interested in the molecular mechanisms by which pro-inflammatory and pro- resolving GPCRs sense diverse signaling molecules and transduce chemical signals across the cell membrane to regulate inflammation. We employ a combination of research approaches in structural biology including cryo- electron microscopy (cryo-EM), pharmacology, and computational biology. We are also making efforts to develop novel ligands of those GPCRs as potential new drugs through structure-based approaches. In the last funding period, we have determined structures of several members of a chemotactic GPCR family including the C5a receptor (C5aR), the prostaglandin D2 receptor 2 (DP2), and the formylpeptide receptors bound to diverse agonists or antagonists at different conformational states, which allowed us to define the molecular basis for the action of several drugs and drug candidates. In the current proposal, we will study the signaling and pharmacology of three lipid GPCRs that regulate different aspects of inflammation, the chemerin receptor CMKLR1 (ChemR23), GPR32, and GPR84. Both CMKLR1 and GPR32 are closely related to the C5aR, DP2 and FPRs. They have been shown to respond to resolvins, which are SPMs derived from ω-3 polyunsaturated fatty acids (PUFAs), to induce the resolution of inflammation. In contrast, GPR84 is a newly characterized pro- inflammatory GPCR that can be activated by endogenous medium-chain fatty acids (MCFAs) to augment inflammatory responses and enhance phagocytosis by macrophages. For the next five years, we aim to provide a comprehensive molecular understanding of how diverse lipid, peptide, and synthetic small-molecule ligands act on and regulate the activities of these three lipid GPCRs. Our studies will exploit unique properties of CMKLR1, GPR32, and GPR84 to address several fundamental issues of GPCR signaling and pharmacology including lipid recognition, receptor antagonism, allosteric modulation, and biased signaling. Our research strategies developed in this proposal will be applied to our future research on the structure and pharmacology of other fatty acid receptors (FFARs) in immunometabolism. We will also identify new hit compounds for these GPCRs in the next five years, which will be further developed in future as useful pharmacological tools and potential drugs to control inflammation.


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: 2026 ( Subtotal = $419,909 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	002	8	3/20/2026	NON-COMPETING CONTINUATION	$41,991
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	001	8	1/9/2026	NON-COMPETING CONTINUATION	$377,918
2026	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	7	1/8/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $419,909

Issue Date FY: 2025 ( Subtotal = $419,909 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	003	7	9/4/2025	NON-COMPETING CONTINUATION	$41,991
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	002	7	12/16/2024	NON-COMPETING CONTINUATION	$377,918
2025	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	6	11/5/2024	COMPETING CONTINUATION	$0
2025	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	001	5	12/12/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $419,909

Issue Date FY: 2024 ( Subtotal = $665,864 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	6	12/19/2023	COMPETING CONTINUATION	$434,659
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	001	6	9/12/2024	SUPPLEMENT FOR EXPANSION	$231,205
														Subtotal = $665,864

Issue Date FY: 2022 ( Subtotal = $391,250 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	5	7/26/2022	NON-COMPETING CONTINUATION	$391,250
														Subtotal = $391,250

Issue Date FY: 2021 ( Subtotal = $391,250 )
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	4	7/19/2021	NON-COMPETING CONTINUATION	$391,250
														Subtotal = $391,250

Issue Date FY: 2020 ( Subtotal = $391,250 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	000	3	7/15/2020	NON-COMPETING CONTINUATION	$391,250
														Subtotal = $391,250

Issue Date FY: 2019 ( Subtotal = $439,950 )
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	000	1	6/7/2019	SUPPLEMENT FOR EXPANSION	$48,700
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	001	2	7/30/2019	NON-COMPETING CONTINUATION	$391,250
														Subtotal = $439,950

Issue Date FY: 2018 ( Subtotal = $391,250 )
2018	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	000	1	7/31/2018	NEW	$391,250
														Subtotal = $391,250

Grand Total All Awards = $3,510,632

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Structure, pharmacology and signaling of G protein-coupled receptors (GPCRs) in inflammation

Award Number: R35GM128641

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2018

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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