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Principal Investigator: Eva de Alba Bastarrechea
Organization: UNIVERSITY OF CALIFORNIA, MERCED
Fiscal Year: 2024
Award: $183,186
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
Multiprotein complexes known as inflammasomes form in innate immune cells to trigger inflammation upon
detection of pathogens or tissue damage. Abnormal inflammasome activation leads to chronic inflammation,
which is the culprit of numerous life-threatening diseases such as cancer, diabetes, cardiovascular disorders,
and the cytokine storm in SARS-CoV-2 infection. Inflammasome assembly is controlled by protein-protein
interactions as it requires the self-association and oligomerization of multiple copies of three proteins: sensors
to detect danger signals, a protease to activate inflammatory factors, and the adaptor protein ASC to connect
sensor and protease. Inflammasome formation leads to plasma membrane rupture and concomitant cell death,
thus resulting in the release of proinflammatory cytokines and inflammasome particles to the extracellular
environment. These extracellular inflammasomes are internalized by nearby cells to perpetuate and amplify the
inflammatory response. Removing or sequestering extracellular inflammasomes will likely inhibit or reduce
inflammation. Therefore, extracellular inflammasomes are potential therapeutic targets. Our laboratory’s
extensive experience on the function and structure of the adaptor ASC, and its interactions with other
inflammasome proteins, has led us to create hydrogels designed to form specific protein-protein interactions with
inflammasomes; thus, they have the potential to broadly inhibit inflammation by effectively capturing and
removing extracellular inflammasomes. This project focuses on identifying the hydrogelation factors leading to
optimum biding of inflammasome particles in cell-free systems (Aim 1); and determining the anti-inflammatory
efficiency of the hydrogels in the presence of activated innate immune cells (Aim 2). Our experimental plan will
combine cell biology and biochemical approaches, including live/dead cell imaging, flow cytometry,
immunoblotting, enzyme-linked immunosorbent assays and fluorescence spectroscopy. Overall, we expect to
develop a hydrogel technology of broad applicability to reduce inflammation in the absence of drug loading by
targeting the inflammasome, which is implicated in many inflammatory diseases.
Terms: <3-D structure><3-dimensional structure><3D structure><Adaptor Protein><Adaptor Protein Gene><Adaptor Signaling Protein><Adaptor Signaling Protein Gene><Adopted><Amino Acid Sequence><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Apoptosis-Related Cysteine Protease Caspase 1><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Atrophic Arthritis><Binding><Biochemical><Body Tissues><CASP-1><CASP1><CASP1 gene><COPD><COVID-19 infection><COVID-19 virus infection><COVID19 infection><Cancers><Cardiovascular Diseases><Caspase-1><Caspase-1 Gene><Cell Body><Cell Communication and Signaling><Cell Death><Cell Signaling><Cell membrane><Cell-Free System><Cellfree System><Cells><Cellular biology><Chronic><Chronic Obstruction Pulmonary Disease><Chronic Obstructive Lung Disease><Chronic Obstructive Pulmonary Disease><Cytoplasmic Membrane><DNA><Data><Deoxyribonucleic Acid><Dependence><Detection><Diabetes Mellitus><Diameter><Disease><Disorder><Drugs><Dysfunction><ELISA><Environment><Enzyme-Linked Immunosorbent Assay><Esteroproteases><Filament><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Fluorescence><Fluorescence Light Microscopy><Fluorescence Microscopy><Fluorescence Spectroscopy><Functional disorder><Funding><Future><Glues><Hydrogels><ICE Protease><IL-1 beta Convertase><IL-1 beta-Converting Enzyme><IL-1BC><IL-1b Converting Enzyme><IL1B-Convertase><IL1BC><IL1BCE><Immune><Immunes><Immunoblotting><Implant><Infection><Inflammasome><Inflammation><Inflammatory><Inflammatory Response><Injectable><Injury><Interleukin 1-B Converting Enzyme><Interleukin 1-Beta Convertase><Interleukin-1 Beta Converting Enzyme><Interleukin-1 Converting Enzyme><Intracellular Communication and Signaling><Isoforms><Knowledge><Label><Laboratories><Life><Macromolecular Protein Complexes><Macrophage><Malignant Neoplasms><Malignant Tumor><Measures><Medication><Molecular><Molecular Interaction><Monitor><Multiprotein Complexes><Mφ><NIH><National Institutes of Health><Nervous System Diseases><Nervous System Disorder><Neurologic Disorders><Neurological Disorders><Organ><Pathogen detection><Pathogenicity><Penetration><Peptidases><Peptide Hydrolases><Pharmaceutical Preparations><Physiopathology><Plasma Membrane><Play><Primary Protein Structure><Protease Gene><Proteases><Protein Engineering><Protein Isoforms><Proteinases><Proteins><Proteolytic Enzymes><Public Health><Regulation><Reporting><Research><Resolution><Rheumatoid Arthritis><Role><Rupture><SARS-CoV-2 infection><SARS-CoV2 infection><Severe acute respiratory syndrome coronavirus 2 infection><Signal Transduction><Signal Transduction Systems><Signaling><Sodium Chloride><Structure><Technology><Temperature><Testing><Time><Tissues><United States National Institutes of Health><Western Blotting><Western Immunoblotting><adapter protein><atheromatosis><atherosclerotic disease><atherosclerotic vascular disease><biological signal transduction><cardiovascular disorder><cell biology><cell imaging><cellular imaging><chronic obstructive pulmonary disorder><coronavirus disease 2019 infection><cytokine><cytokine release syndrome><cytokine storm><design><designing><diabetes><direct application><drug/agent><enzyme linked immunoassay><experience><extracellular><flow cytophotometry><genetic protein engineering><human disease><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><injuries><macromolecular assembly><malignancy><meter><necrocytosis><neoplasm/cancer><neurological disease><optic trap><optical traps><particle><pathogen><pathophysiology><plasmalemma><protein blotting><protein complex><protein design><protein protein interaction><protein sequence><recruit><resolutions><rheumatic arthritis><salt><self assembly><sensor><social role><super high resolution><superresolution><therapeutic target><three dimensional structure><ultra high resolution>