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Principal Investigator: Jacob Albright
Organization: UNIVERSITY OF MONTANA
Fiscal Year: 2024
Award: $38,800
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <4-Sphingenine><Accounting><Acid Ceramidase><Acute><Alveolar Macrophages><Amyloid (Aβ) plaques><Amyloid Plaques><Apoptotic><Asbestos><Automobile Driving><Beta Proprotein Interleukin 1><Biological><Biophysics><CBP-30><CBP-35><CBP35><Carbohydrate-Binding Protein 35><Cathepsin B1><Cathepsins B><Cell Death><Cell Function><Cell Growth in Number><Cell Membrane Permeability><Cell Multiplication><Cell Physiology><Cell Process><Cell Proliferation><Cellular Function><Cellular Physiology><Cellular Process><Cellular Proliferation><Ceramide Trihexosidase><Ceramides><Cessation of life><Cholesterol><Chronic><Chronic Disease><Chronic Illness><Confocal Microscopy><Cristobalite><Cytosol><Death><Disease><Disorder><Drugs><EC 3.4.22.1><Economic Burden><Environment><Enzyme Gene><Enzymes><Epsilon-Binding Protein><Event><Exposure to><Failure><Fiber><Fluorescence Anisotropy><Galectin 3><Goals><HL-29><Health Care Costs><Health Costs><Healthcare Costs><IL-1 beta><IL-1 β><IL-1-b><IL-1β><IL1-Beta><IL1-β><IL1B Protein><IL1F2><IL1β><IgE Binding Protein><IgEBP><Imidobenzyle><Imipramine><Imizin><Inflammasome><Inflammation><Inflammatory><Interleukin 1beta><Interleukin-1 beta><Interleukin-1β><Intermediary Metabolism><Knowledge><L-29 Lectin><L-31><L-34><L30 Lectin><LGALS3><Lipids><Lung Diseases><Lung Tissue Fibrosis><Lysosomes><Mac-2 Antigen><Macromolecular Protein Complexes><Macrophage><Macrophage Activation><Macrophage-2 Antigen><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measurement><Measures><Mediating><Mediator><Medical><Medication><Membrane><Metabolic Processes><Metabolism><Methods><Mice><Mice Mammals><Modeling><Molecular><Multiprotein Complexes><Murine><Mus><Mφ><Neuritic Plaques><Norchlorimipramine><Occupational><Outcome><Pathologic><Pathologic Processes><Pathological Processes><Pathway interactions><Permeability><Pharmaceutical Preparations><Play><Preinterleukin 1 Beta><Protocol><Protocols documentation><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Fibrosis><Pulmonary Macrophages><Reporting><Research><Resistance><Role><Sand><Senile Plaques><Series><Silica><Silicon Dioxide><Silicosis><Sphingolipids><Sphingomyelins><Sphingosine><Subcellular Process><Techniques><Testing><Tissue Model><Tofranil><Toxic effect><Toxicities><Tridymite><Urate><V-ATPase><V-type ATPase><Work><acid sphingomyelinase><amphiphilicity><amyloid beta plaque><amyloid-b plaque><aβ plaques><bafilomycin A1><biologic><biophysical foundation><biophysical principles><biophysical sciences><chronic disorder><chronic inflammatory disease><combat><cored plaque><cytokine><design><designing><diffuse plaque><disease model><disease of the lung><disorder model><disorder of the lung><driving><drug/agent><fat metabolism><fibrosis in the lung><galactosylgalactosylglucosylceramidase><inflammatory lung disease><inhibitor><injury to tissue><lipid metabolism><lipidomics><lung disorder><lung fibrosis><lysosome membrane><membrane model><membrane permeability><membrane structure><metal oxide><mortality><nano particle><nano-sized particle><nanoparticle><nanosized particle><necrocytosis><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><particle><pathway><prevent><preventing><resistant><small molecular inhibitor><small molecule inhibitor><social role><sphingosine 1-phosphate><sphingosine kinase><therapeutically effective><time use><tissue injury><vacuolar ATPase><vacuolar H+-ATPase><vacuolar membrane H(+)-ATPase>