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Revealing the Mechanisms of Cleaved and Intact GSDMD Pore Formation and Membrane Rupture

Award Number: F31AI191410
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/01/2025
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Revealing the Mechanisms of Cleaved and Intact GSDMD Pore Formation and Membrane Rupture - ABSTRACT Humans are exposed to hundreds of millions of pathogens daily. The innate immune system is one of two immune arms and the first line of host defense. It quickly recognizes danger stimuli: damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). Sensor proteins including NLRP3 (nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat domain (LRR)-, and pyrin domain-containing protein 3) can detect PAMPs and DAMPs, resulting in the activation of supramolecular protein-signaling complexes called the NLRP3 inflammasome. Upon stimulation, NLRP3 interacts with the centrosomal NIMA-related kinase 7 (NEK7) and oligomerizes into a complex essential for recruiting the ASC adaptor protein, generating functionally active NLRP3 inflammasome. The assembled NLRP3 inflammasome specks recruit and activate caspase-1, a protease that cleaves pro-inflammatory cytokines interleukin (IL)-1β and IL-18 generating active cytokines. In addition to cytokine activation, caspase-1 cleaves the pore-forming protein gasdermin D (GSDMD), facilitating GSDMD-dependent pyroptotic cell death and secretion of IL-1β and IL-18 to release inflammatory signals. While imperative to the inflammatory response and host defense, aberrant hyperactivation or gain-of-function mutations in inflammasome proteins can cause constitutive cytokine activation and pyroptosis, leading to human diseases such as inflammatory bowel disease, cardiovascular disease, gout, and other rare autoinflammatory disorders. Moreover, inhibiting the inflammasome pathway is a therapeutic strategy for preventing lethal septic shock. Despite its therapeutic potential, many mechanistic details underlying the activation of inflammasomes remain unknown. Herein, I propose to elucidate the molecular mechanisms underlying the activation and regulation of the inflammasome executioner protein GSDMD. I aim to interrogate this complex system through a combination of biochemistry, biophysics, and cell biology. Completion of these independent aims will illuminate the mechanisms of how GSDMs are regulated and exert their pore- forming activity, which will not only provide new insights into pyroptosis but also afford new therapeutic strategies for treating inflammasome-related and pyroptosis-related 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: 2026 ( Subtotal = $38,123 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	2/13/2026	NON-COMPETING CONTINUATION	$37,547
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	2	4/2/2026	NON-COMPETING CONTINUATION	$576
														Subtotal = $38,123

Issue Date FY: 2025 ( Subtotal = $44,020 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	1	1/15/2025	NEW	$0
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	002	1	7/24/2025	NEW	$564
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	1/15/2025	NEW	$43,456
														Subtotal = $44,020

Grand Total All Awards = $82,143

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Revealing the Mechanisms of Cleaved and Intact GSDMD Pore Formation and Membrane Rupture

Award Number: F31AI191410

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/01/2025

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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