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BK potassium channel activity in cSiO2-induced lysosome membrane permeability and inflammation

Award Number: F31ES033562
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2023

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BK potassium channel activity in cSiO2-induced lysosome membrane permeability and inflammation - Abstract Chronic inflammation is a significant contributing factor to pulmonary and other diseases. One trigger of chronic inflammation is respirable crystalline silica (cSiO2) in occupational settings, and, therefore, presents a useful model to investigate the mechanisms of unresolved, lysosome dysfunction-mediated inflammation. cSiO2 causes phagolysosomal membrane permeabilization (LMP) and NLRP3 inflammasome activation in alveolar macrophages. The activated inflammasome cleaves caspase-1 and triggers inflammation through the secretion of interleukin 1b (IL-1b) and interleukin 18 (IL-18). The lysosome’s role in NLRP3 inflammasome activity and its contributions to macrophage homeostasis make it of significant interest in the development of therapeutic targets for chronic inflammatory human health conditions. Within the lysosome, ion channels are indispensable to its function. This research will investigate the role of the lysosomal potassium (K+) channel in LMP and how it contributes to NLRP3-mediated inflammation. Current literature shows that particulate-induced NLRP3 inflammasome activity correlates to a decrease in cytosolic K+, which is assumed to be K+ efflux from the cytosol to the extracellular matrix. However, the contribution of lysosomal K+ channels to the decrease of cytosolic K+ in NLPR3 inflammasome activation must be considered. Our preliminary results indicate that K+ movement into the lysosome through the lysosomal big conductance potassium (BK) channel precedes LMP and NLRP3 inflammasome activity. Blocking lysosomal BK channel activity reduces cSiO2-induced cell death and IL-1b release, suggesting lysosomal ion channel involvement in the mechanisms in LMP. This project will address the hypothesis that cSiO2 interacts with the lysosomal membrane and initiates changes in the lysosomal membrane lipid order and promotes lysosomal BK channel activity, a decrease in cytosolic K+, LMP, and NLRP3 inflammasome activity.


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 = $0 )
2024	2022	UNIVERSITY OF MONTANA	32 CAMPUS DR	MISSOULA	MT	59812	MISSOULA	USA	Environmental Health	000	2	6/24/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	UNIVERSITY OF MONTANA	32 CAMPUS DR	MISSOULA	MT	59812	MISSOULA	USA	Environmental Health	000	2	8/28/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $39,066 )
2022	2022	UNIVERSITY OF MONTANA	32 CAMPUS DR MAIN HALL	MISSOULA	MT	59812	MISSOULA	USA	Environmental Health	000	2	8/15/2022	NON-COMPETING CONTINUATION	$39,066
														Subtotal = $39,066

Issue Date FY: 2021 ( Subtotal = $37,823 )
2021	2021	UNIVERSITY OF MONTANA	32 CAMPUS DR MAIN HALL	MISSOULA	MT	59812	MISSOULA	USA	Environmental Health	000	1	8/31/2021	NEW	$37,823
2021	2021	UNIVERSITY OF MONTANA	32 CAMPUS DR MAIN HALL	MISSOULA	MT	59812	MISSOULA	USA	Environmental Health	001	1	8/31/2021	NEW	$0
														Subtotal = $37,823

Grand Total All Awards = $76,889

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BK potassium channel activity in cSiO2-induced lysosome membrane permeability and inflammation

Award Number: F31ES033562

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2023

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