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Sphingomyelin Metabolism Impacts on Crystalline Silica-Induced Outcomes

Award Number: F31AI181539
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/12/2024
PERIOD OF PERFORMANCE END DATE: 08/11/2026

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Sphingomyelin Metabolism Impacts on Crystalline Silica-Induced Outcomes - Abstract There are numerous examples of endogenous and exogenous particle-induced chronic inflammation. One model of chronic environmentally-induced inflammation is driven by exposure to crystalline silica particles. There are various occupational lung diseases that arise from exposure to exogenous particles such as asbestos fibers and crystalline silica (cSiO2) leading to chronic inflammation and lung fibrosis, however there are insufficient treatment options. A commonality of particle-induced inflammation is lysosome membrane permeabilization (LMP), in macrophages. Previous studies have shown that cSiO2-induced LMP allows lysosomal enzymes to leak out into the cytosol where they can trigger cell death pathways and activate the NLRP3 inflammasome, a multiprotein complex that is responsible for the processing and release of IL-1β from macrophages. IL-1β is a potent proinflammatory cytokine that is involved in nearly all models of chronic inflammation and subsequent diseases. Therefore, understanding the mechanisms of cSiO2-induced LMP and downstream IL-1β release could provide information for identifying novel therapies that target chronic inflammation. The goal of this proposal is to further elucidate the interactions between cSiO2 particles and the inner lysosomal membrane leading to LMP with the ultimate goal of blocking LMP and downstream inflammation. Current research suggests that sphingomyelin metabolism mediates numerous vital and pathological cell processes. My preliminary results suggest that disruptions in sphingomyelin metabolism can prevent cSiO2-induced IL-1β release in macrophages and change the lipid content of isolated lysosomes by increasing sphingomyelin and cholesterol levels while decreasing ceramide. However, critical details are still needed to fully characterize the involvement of sphingomyelin metabolism in cSiO2-induced inflammation. Furthermore, the biophysical changes induced by cSiO2 on model membranes have been described but not in isolated lysosomes. Therefore, the studies proposed in this work will elucidate the biophysical changes caused by cSiO2 in isolated lysosome membranes that result in LMP and determine the involvement of sphingomyelin metabolism by comprehensively analyzing changes to the lipid profile of isolated lysosomes using a lipidomics approach. Finally, by using multiple inhibitory techniques to disrupt sphingomyelin metabolism at specific steps, previously unexplained mechanistic details of cSiO2- induced inflammation and cell death will be determined. Taken together, these novel studies will provide new information on mechanisms of particle-induced activation of macrophages that will provide potential new therapeutic targets.


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 = $39,457 )
2025	2025	UNIVERSITY OF MONTANA	32 CAMPUS DR	MISSOULA	MT	59812	MISSOULA	USA	Allergy and Infectious Diseases Research	000	2	8/27/2025	NON-COMPETING CONTINUATION	$39,457
														Subtotal = $39,457

Issue Date FY: 2024 ( Subtotal = $38,800 )
2024	2024	UNIVERSITY OF MONTANA	32 CAMPUS DR	MISSOULA	MT	59812	MISSOULA	USA	Allergy and Infectious Diseases Research	001	1	8/7/2024	NEW	$0
2024	2024	UNIVERSITY OF MONTANA	32 CAMPUS DR	MISSOULA	MT	59812	MISSOULA	USA	Allergy and Infectious Diseases Research	000	1	8/7/2024	NEW	$38,800
														Subtotal = $38,800

Grand Total All Awards = $78,257

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Sphingomyelin Metabolism Impacts on Crystalline Silica-Induced Outcomes

Award Number: F31AI181539

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/12/2024

PERIOD OF PERFORMANCE END DATE: 08/11/2026

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