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Caspase-1 Activation by the Inflammasomes

Award Number: R01AR078440
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Caspase-1 Activation by the Inflammasomes - Inflammasomes are multi-protein complexes that assemble to activate caspase-1 in response to tissue damage and infection by microbial or viral pathogens. Once activated, caspase-1 processes the inactive proforms of interleukin-1β (IL-1β) and interleukin-18 (IL-18) to produce the active pro-inflammatory cytokines IL-1β and IL- 18, respectively. In addition, caspase-1 processes the gasdermin protein GSDMD to induce pyroptosis or inflammatory cell death. The NLRP3 inflammasome is unique among the different inflammasomes in that it is activated by diverse pathogen-associated and danger-associated molecular patterns (PAMPs and DAMPs) derived from infection with microbial pathogens, or tissue damage. As a result, uncontrolled NLRP3 activation can lead to a number of human inflammatory diseases, including gout, arthritis, atherosclerosis, and type 2 diabetes. The mechanism of NLRP3 activation by these seemingly unrelated stimuli is poorly understood but is currently believed to require two distinct signals; a priming signal or “signal 1” produced by Toll-like receptors (TLRs) and an activation signal or “signal 2” that induces fragmentation of trans Golgi network (TGN) and binding to NEK7. Studies in the applicant's laboratory demonstrated that signal 1 induces post-translational modification (PTM) of NLRP3 at critical sites via the MyD88 and TRIF signaling pathways and partial oligomerization of NLRP3. In this application, studies are proposed to elucidate how TLR-induced PTM contributes to posttranslational priming of the NLRP3 inflammasome by employing mass spectrometry to identify and characterize all critical changes in the phosphorylation and other PTM profile of NLRP3 induced by signal 1, and investigating how these changes contribute to activation of NLRP3. Additional aims will investigate the effect of signal 1 and signal 1-induced PTM on NLRP3 association with dispersed TGN and NEK7, and identify the TGN-associated kinases required for final assembly and activation of the inflammasome. Finally, preliminary evidence suggest that kinases involved in the regulation of intracellular ion homeostasis exert negative control on activation of NLRP3 by signal 2. Thus, additional experiments will investigate how signaling from these kinases in macrophages impacts NEK7 phosphorylation and interaction with NLRP3, and how genetic deficiency in these kinases impacts NLRP3-mediated pro-inflammatory responses to PAMPs and DAMPs in vivo. Results from this research will provide fundamental new insights into the pathways that regulate the assembly and activation of the NLRP3 inflammasome, and the cellular mechanisms that control its activation. Successful completion of this study should have a high impact on the field by providing a unifying paradigm for how NLRP3 can be regulated by an exceptionally diverse group of activating stimuli. Understanding these mechanisms is of great scientific and health significance as this should better our understanding of the molecular basis of NLRP3-related diseases and should in the long term help in the development of therapeutics to alleviate these inflammatory 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 = $549,226 )
2025	2025	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	4/30/2025	NON-COMPETING CONTINUATION	$549,226
														Subtotal = $549,226

Issue Date FY: 2024 ( Subtotal = $515,961 )
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	5/3/2024	NON-COMPETING CONTINUATION	$478,728
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	6/6/2024	NON-COMPETING CONTINUATION	$37,233
														Subtotal = $515,961

Issue Date FY: 2023 ( Subtotal = $531,919 )
2023	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	4/26/2023	NON-COMPETING CONTINUATION	$531,919
														Subtotal = $531,919

Issue Date FY: 2022 ( Subtotal = $526,598 )
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	4/29/2022	NON-COMPETING CONTINUATION	$526,598
														Subtotal = $526,598

Issue Date FY: 2021 ( Subtotal = $531,919 )
2021	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	5/5/2021	NEW	$531,919
														Subtotal = $531,919

Grand Total All Awards = $2,655,623

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Caspase-1 Activation by the Inflammasomes

Award Number: R01AR078440

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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