Thursday, January 1, 2026 1/1/2026

Membrane potential and Calcium Signaling in Neutrophil Development and Inflammation

Award Number: R01AI166793
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: 11/19/2021
PERIOD OF PERFORMANCE END DATE: 10/31/2026

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Membrane potential and Calcium Signaling in Neutrophil Development and Inflammation - PROJECT SUMMARY Neutrophils are essential for host defense against bacteria, however toxic neutrophil mediators such as reactive oxygen radicals, granule enzymes and neutrophil extracellular traps contribute the pathogenesis of acute and chronic inflammatory diseases. While the ability of neutrophils to phagocytose and kill pathogens has been known for over 100 years, our knowledge of the molecular mechanisms guiding neutrophil activation lags significantly behind that of other immune cells, precluding the development of strategic therapeutic interventions targeting neutrophils. Our long-term goal is to define the mechanisms by which ion channels and associated signaling pathways regulate neutrophil activation, and to leverage this knowledge to modify disease. Calcium signals initiated via store-operated calcium entry (SOCE) are required for neutrophil activation. The cell membrane potential directly influences influx of positively charged calcium ions. While the functional role of the cell membrane potential has been extensively studied in excitable cells, little is known about how the membrane potential modifies cellular processes in neutrophils in the context of development and inflammation. This proposal is based on four fundamental observations from our laboratory: 1) ORAI1 and ORAI2 calcium channels are critical for neutrophil SOCE and host defense during infection with S. aureus. 2) Calcium responses in mouse neutrophils are heterogenous, with the magnitude of the calcium response modulated in part by differential regulation of the cell membrane potential. 3) Expression of the calcium- activated potassium channel KCa3.1 (Kcnn4) drives cell hyperpolarization and enhanced SOCE in a subset of neutrophils. 4) The membrane potential-SOCE relationship is modulated during neutrophil development and emergency granulopoiesis. Moreover, we have observed that a S. aureus pore-forming toxin manipulates the neutrophil membrane potential and SOCE. Together these observations illustrate that the membrane potential is a key modifier of calcium-dependent neutrophil function, and suggest that this pathway is a strategic target of human pathogenic bacteria that secrete pore-forming cytotoxins to overcome host neutrophil defenses. The objective of this proposal is to characterize the mechanisms by which membrane potential regulates SOCE during neutrophil development and inflammation. We will test the central hypothesis that the membrane potential is a critical modifier of neutrophil calcium signaling in mature neutrophils and homeostatic and emergency granulopoiesis. In Aims 1 and 2 we will investigate the role of KCa3.1 in neutrophil SOCE and calcium-dependent activation in mature and developing neutrophils. In Aim 3 we will expand these studies to investigate how exogenous manipulation of the cell membrane potential by bacterial pore-forming toxins disrupts calcium-dependent neutrophil function. The insight derived from these studies is anticipated to engender new clinical opportunities for modulation of neutrophil-dependent infectious and inflammatory disease, and potentially inform a broader understanding of membrane potential in immune cell function.


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 = $388,750 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	5	11/26/2025	NON-COMPETING CONTINUATION	$388,750
														Subtotal = $388,750

Issue Date FY: 2025 ( Subtotal = $377,088 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	4	1/15/2025	NON-COMPETING CONTINUATION	$377,088
														Subtotal = $377,088

Issue Date FY: 2024 ( Subtotal = $388,750 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	001	3	5/13/2024	NON-COMPETING CONTINUATION	$38,875
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	3	10/27/2023	NON-COMPETING CONTINUATION	$349,875
														Subtotal = $388,750

Issue Date FY: 2023 ( Subtotal = $392,084 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	2	10/18/2022	NON-COMPETING CONTINUATION	$392,084
														Subtotal = $392,084

Issue Date FY: 2022 ( Subtotal = $393,750 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	001	1	12/23/2021	NEW	$0
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	1	11/18/2021	NEW	$393,750
														Subtotal = $393,750

Grand Total All Awards = $1,940,422

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Membrane potential and Calcium Signaling in Neutrophil Development and Inflammation

Award Number: R01AI166793

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: 11/19/2021

PERIOD OF PERFORMANCE END DATE: 10/31/2026

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